Next Article in Journal
Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death
Next Article in Special Issue
EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats
Previous Article in Journal
E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT
Previous Article in Special Issue
The Endothelium as a Driver of Liver Fibrosis and Regeneration
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond

1
Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
2
Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
3
Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
4
Genomics and Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
5
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
*
Author to whom correspondence should be addressed.
Cells 2020, 9(4), 1041; https://doi.org/10.3390/cells9041041
Submission received: 1 April 2020 / Revised: 15 April 2020 / Accepted: 18 April 2020 / Published: 22 April 2020

Abstract

:
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and ranges from steatosis to steatohepatitis and to liver fibrosis. Lipotoxicity in hepatocytes, elevated oxidative stress and the activation of proinflammatory mediators of Kupffer cells, and fibrogenic pathways of activated hepatic stellate cells can contribute to the development of NAFLD. MicroRNAs (miRs) play a crucial role in the dysregulated metabolism and inflammatory signaling connected with NAFLD and its progression towards more severe stages. Of note, the protective effect of non-coding miR-29a on liver damage and its versatile action on epigenetic activity, mitochondrial homeostasis and immunomodulation may improve our perception of the pathogenesis of NAFLD. Herein, we review the biological functions of critical miRs in NAFLD, as well as highlight the emerging role of miR-29a in therapeutic application and the recent advances in molecular mechanisms underlying its liver protective effect.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use [1]. NAFLD is a hepatic manifestation of the metabolic syndrome [2] and is closely associated with cardio- and neurological complications, including cardiovascular disease, hypertension, cognitive dysfunction, and ischemic stroke [3,4]. NAFLD may result from “multiple and parallel hits” like lipotoxicity caused by the excessively elevated uptake of fatty acid (FA) into hepatocytes, subsequently elevated oxidative stress, and the activation of proinflammatory mediators of Kupffer cells (KC), as well as fibrogenic pathways of activated hepatic stellar cells (HSC), leading to non-alcoholic steatohepatitis (NASH) and non-alcoholic steatofibrosis (NASF) [5]. Considered a key predisposing factor for cirrhosis, NASH is implicated as a risk factor for non-viral hepatitis-related hepatocellular carcinoma (HCC) [6].
MicroRNAs (miRs) are small non-coding RNAs with about 22 nucleotides that have been found to have a regulatory role in transcriptional control mechanisms in guiding metabolic homeostasis. MiRs are first transcribed by RNA polymerase II or III in the nucleus to generate primary miRs (pri-miRs) which will be consequently processed to become precursor miRNAs (pre-miRs) [7]. The miRs then bind to 3′untranslated region (3′UTR) of target mRNA(s) and can lead to mRNA degradation or translational repression [8]. Despite of this dogmatic view in the repressive activity, some miRs acting to enhance gene expression has been recognized [9]. In addition, other mechanisms have recently been reported, such as miRNAs binding to 5′UTR or coding sequence of mRNA [10], Toll-like receptors [11,12] or mitochondrial transcripts [13]. There are increasing evidences reporting that some miRs regulate pathways governing lipid metabolism, oxidative stress and inflammation in the liver, playing a crucial role in the pathophysiology of NAFLD [14,15]. For example, miR-122, miR-34a, miR-33, miR-21, and miR-29 were acknowledged for their regulatory role in hepatic functions and for their therapeutic potential [14,15,16].
The miR-29 family in human includes miR-29a, -29b, and -29c. Mature miR-29s are highly similar between human, mouse, and rat [17]. Pathophysiological disturbance of various tissue or cell types could contribute to the alteration of circulating miR-29a level, as miR-29a level has been shown to corelate with diverse human diseases, including Alzheimer’s disease [18], Parkinson’s disease [19], ankylosing spondylitis [20], atherosclerosis [21], atrial fibrillation [22], active pulmonary tuberculosis [23], thoracic aneurysms [24], tendon disease [25], diabetes [26], scleroderma [27] and cholestatic pediatric liver disease [28].
In addition, miR-29a was tightly connected with diagnostic relevance of NAFLD [29], NASH [30], and liver fibrosis [30,31,32], as well as aggressiveness and prognosis of HCC [33,34,35,36]. Importantly, several lines of study have indicated the emerging roles of miR-29a through multiple signaling networks in experimental models simulating liver diseases, including NAFLD, NASH, fibrosis, and HCC (Table 1). In this review, we focus on the latest findings regarding the biological role of miR-29a, as well as some important miRs in NAFLD. We also discuss recent advances in the molecular mechanisms underlying miR-29a-mediated protective effects against hepatic dysfunction.

2. MiRs as Markers in Liver Disease

The liver serves as a central organ in energy metabolism as it mainly contributes to regulate absorptive glucose storage and post-absorptive glucose release, amino acid metabolism, and lipid/lipoprotein metabolism. Since Lee et al. firstly identified the critical function of miRs in regulating the development of C. elegans [57], mounting lines of evidence have revealed that miRs are pivotal for controlling metabolic homeostasis and represents relevance in diagnosing liver diseases. miR-122, which is the most abundant miRs in the liver, is involved in hepatic cholesterol and lipid metabolism [58], and presented an increased level in circulation in the context of NAFLD [59,60,61,62], making a well predictive panel when combined with miR-29a [29]. Moreover, dysregulated level of circulating miRs were also reported, including miR-122 [29], miR-34a [61,63], miR-33 [62], miR-21 [64], miR-192 [60], miR-221/222 [65], miR-375 [59], and miR-802 [66]. Table 2 exhibits a non-exhaustive list of miRs of important in the context of liver diseases.
In 2011, Roderburg et al. identified miR-29a as a non-invasive biomarker for liver fibrosis in cirrhosis patients and mouse model [32]. In the following year, Zhu et al. discovered the role of miR-29a as a prognostic marker in HCC patients receiving surgical resection [35]. At present, growing body of evidence has shown the significance of miR-29a as a diagnostic/prognostic tool in HCC [41,42,47,50,55,67,68,69,70] and alcoholic liver disease [71], as well as NAFLD. In 2017, Lopez-Riera et al. identified circulating miR-29a as one predictor of miRNAs biomarker set in NAFLD patients [72]. Studies from Lambrecht et al. as we as Jampoka et al. highlighted miR-29a as an essential part in predictive algorithm for NAFLD [29,31]. Furthermore, studies using mouse model also confirmed the close involvement of miR-29a in representing the progression of NAFLD [44,73] and NASH [74,75]. A non-exhaustive list of miR-29a with altered level in liver diseases is provided in Table 3.
Table 2. MiRs Implicated in Liver Diseases.
Table 2. MiRs Implicated in Liver Diseases.
microRNAExpressionReference
miR-21Up[64]
miR-33Up[62]
miR-34aUp[61,63,64,76]
miR-103/107Up[77]
miR-122Up[29,59,60,61,63,76]
miR-132Down[78]
miR-146bDown[78,79]
miR-148aDown[80,81]
miR-181aUp[82,83,84]
miR-181dDown[79]
miR-192Up[59,60,63]
miR-197Down[79]
miR-221/222Up[65,85]
miR-375Up[59]
miR-802Up[66]

3. MiR-29a Functions as an Epigenetic Modifier to Mitigate Liver Injury

Epigenetic regulation acts to alter hereditary gene expression by modifying chromatin structure and the DNA methylation and acetylation that is not related to change the primary DNA sequence [86]. Unlike the genome of an organism, the epigenome is not a consistent entity and may be modulated by different intrinsic, chemical, and environmental cues [87], and its changes may be inherited across generations [88]. DNA methyltransferases (DNMTs), such as DNMT1, DNMT3a, and DNMT3b, enable DNA methylation, which is correlated with the conversion of quiescent HSC into hepatic myofibroblasts [89]. DNA methylation inhibitors exert a regulatory effect on hepatic wound healing and fibrogenesis [90,91]. Of particular note, our recent work demonstrated that miR-29a can repress DNMT3b expression by directly targeting its 3′UTR in the murine primary HSC [37]. Overexpression of miR-29a can alleviate steatosis, NASH, and NASF in methionine-choline-deficient diet-fed mice [37]. Another of our studies also showed that overexpression of miR-29a counteracts fibrosis in murine liver by reducing DNMT1 and DNMT3b [39], as well as the down-regulation of methyl CpG binding protein 2 (MeCP2) [38].
On the other hand, histone deacetylase (HDAC) 4, which acts to modify acetylation reactions in histones and non-histone proteins, has also been reported to have a positive role in activating liver fibrosis [92]. HDAC inhibitors administration exerts ameliorative effect both in experimental animal models and in in vitro cellular models of liver and kidney fibrosis [93]. In mechanistical term, miR-29a could exert suppressive effect on HDAC4 expression level by direct targeting 3′UTR of HDAC mRNA. Based on this molecular basis, our study demonstrated that overexpression of miR-29a in mice presents decreased HDAC4 activity and ameliorated liver fibrosis [40].

4. Role of miR-29a in Oxidative Stress and Inflammation

Under normal mitochondrial homeostasis conditions, physiological reactive oxygen species (ROS) can be effectively removed by antioxidant mechanisms and metabolic adaptations that inhibit substrate delivery to the tricarboxylic acid (TCA) cycle, a series of enzyme-catalyzed chemical reactions used by aerobic organisms to release energy [94]. However, in the context of NAFLD, both increased mitochondrial ROS production and the decreased activity of ROS scavenging mechanisms (e.g., glutathione, superoxide dismutase 2, and catalase) can increase oxidative stress, leading to lipid peroxidation, protein oxidation, and DNA oxidation, as well as mitochondrial damage [95,96]. Although the interaction between miR-29a and redox control in mitochondria is not fully understood, mice harbor miR-29a overexpression show mitigation of DNA oxidative damage and decreased stress-inducible marker heme oxidase-1 in NASH model, suggesting its role in neutralizing oxidative stress [37,97].
Elevated oxidative stress has been linked to altered mitochondrial membrane potential, as well as a loss of mitochondrial integrity in NAFLD. For example, cardiolipin, a unique phospholipid found in the inner mitochondrial membrane, is highly sensitive to oxidative stress, resulting in the induction of a mitochondrial permeability transition (MPT) pore opening, which has been suggested to provide routes for the cytosolic release of mitochondrial danger-associated molecular patterns (mtDAMPs) to trigger pro-inflammatory signaling [98,99,100]. For one, mtDNA that has escaped from mitochondria can activate innate immune signaling through NOD-like receptor family pyrin domain containing 3 (NLRP3) and toll-like receptors (TLRs) [101,102]. In high-fat diet (HFD)-fed mice, mtDNA has been shown to interact with the TLR9 on KC and HSC once released from damaged hepatocytes to trigger the signaling of innate immune and fibrogenesis, as has been suggested to occur in the pathogenesis of NASH [102,103,104]. The extracellular release of a mtDNA-associated protein, mitochondrial transcription factor A (TFAM), can also act as a mtDAMP to provoke pro-inflammatory macrophage activity [105]. mtdsRNA has been recently recognized as a novel mtDAMP that interacts with the dsRNA sensor to trigger innate immune signaling. In an alcoholic liver disease model, hepatocytes generate exosomal mtdsRNA to mediate TLR3 activation and subsequent IL-1β expression in KC [106]. Mitochondrial N-formyl peptides were released from hepatocyte trigger formyl peptide receptor 1 on KC, subsequently stimulating NF-κB activity [5]. Our recent work demonstrated that WT mice fed with HFD developed hepatic inflammation and fibrosis and had increased mtDNA and TFAM in the liver tissue, while those same phenomena in miR-29a transgene mice fed with HFD are greatly reduced [44], indicating that miR-29a may exert an anti-inflammatory effect on the pathogenesis of NAFLD by restricting mtDAMPs. Nevertheless, how miR-29a performs on the mitochondrial restrictive mechanism over these danger signal molecules warrants further study.
Some other miRs also present impacts on pathways mastering mitochondrial functions in the liver. MiR-122 was shown to be required for mitochondrial translation of respiratory proteins, improvement of mitochondrial respiratory enzyme activity and enhancement of mitochondrial proteostasis in the liver [107]. Inhibition of miR-34a was shown to mitigate steatosis in an experimental NAFLD model [108]. As miR-34a presents repressive activity on PPARα by direct association with its mRNA 3′UTR [108], the consequence of miR-34a inhibition could be mediated by an increase of PPARα level, resulting in increased mitochondrial biogenesis, decreased oxidative stress, and reduced inflammatory response. In a similar manner, miR-21 also play a negative role through suppresses PPARα. Inhibition of miR-21 restores PPARα level to exert protective effect on liver inflammation and fibrosis in an experimental mouse NASH [109].

5. Role of miR-29a in Mitochondrial Metabolism

Mitochondrial dysfunction in hepatocytes is a major hallmark of NAFLD [110,111]. While the exact mechanism underlying hepatic mitochondrial dysfunction during NAFLD is not fully understood, one possible reason may be that the HFD-caused flux of free FA into the liver leads to lowered mitochondrial respiratory chain activity, incomplete β-oxidation, decreased ATP synthesis, and dysregulated TCA cycle metabolism, all of which may bring about oxidative stress and lipotoxicity which can contribute to hepatic inflammation, insulin resistance and fibrogenic signaling [112,113].
CD36, an FA translocase, acts as a multifunctional membrane protein that facilitates the uptake of long-chain FA [114]. CD36 is a shared target of LXR, PXR, and PPAR-γ in their mediation of lipid homeostasis [115]. CD36 upregulation has been shown to be coupled with the blunted breakdown of hepatic triglyceride in mice fed an HFD, while CD36 also binds to ox-LDL in the liver [116]. Furthermore, higher plasma concentrations of CD36 were associated with body adiposity, reflecting more severe liver damage in NAFLD in humans [117]. The knockdown of CD36 contributes to improving lipid accumulation in the human hepatic cell line HepG2 [118], suggesting that the liver-specific knockout of CD36 decreases hepatic lipid levels, increases FA oxidation (FAO), and reduces liver inflammatory markers in HF diet-induced steatosis [119]. FAO primarily occurs in mitochondria, as well as in peroxisomes and cytochromes [120,121]. Mitochondrial dysfunction is an important feature of excessive FA influx, while increased FAO produces ROS and induces oxidative stress [122]. This imbalanced redox status can further promote damage to the mitochondrial membranes, leading to compromised liver function [123]. Cholesterol, especially oxidized (ox)-LDL, can recruit infiltrating macrophages and regenerate KC to contribute to the progression of NASH [124]. CD36-mediated ox-LDL also triggers CEBP-β expression to directly upregulate Nogo-B and promote lipophagy, causing lysophosphatidic acid-enhanced yes-associated protein 1 (YAP) oncogenic activity, which subsequently induces carcinogenetic signaling for NAFLD-associated HCC [2]. Ho et al. also revealed the periportal presents free cholesterol and ox-LDL accumulation that is associated with regional HSC activation and liver fibrosis in both human NAFLD [125] and mice [126]. Furthermore, Kawanishi et al. demonstrated that exercise training inhibits CD36 expression in KC and the liver of HFD and high-fructose water model mice [127].
In 2019, Chen et al. reported that ox-LDL/CD36 signaling in macrophage links dysregulated FA metabolism and oxidative stress from the mitochondria, which drove chronic inflammation in the atherosclerosis model [122]. Our group also discovered that miR-29a protects against glucocorticoid-mediated osteoporosis by suppressing the activity of osteoclasts and differentiating from macrophages [128], thus supporting its role in regulating immune cell activity. As a result, CD36 may play a role in linking FA metabolism with mitochondrial oxidative stress and inflammation, as well as be a promising target for reversing hepatic dysfunction in NAFLD.
On the bioinformatic basis that CD36 is a potential miR-29a target, our recent study further demonstrated that miR-29a in vitro directly binds to mRNA 3′UTR of CD36 and suppresses its expression in HepG2 cells [44]. Under HFD, wild type mice develop steatosis and steatofibrosis and show an increased hepatic CD36 level, as well as elevated mtDAMPs and pro-inflammatory genes, while these phenotypes and markers are significantly reduced in miR-29aTg mice [44]. These findings support that lipid accumulation and hepatic inflammation could be effective counteracted on the basis of modulating the miR-29a/CD36/mitochondria axis (Figure 1). Nevertheless, the role of miR-29a in individual cell types (hepatocyte, KC, and HSC) and how it regulates intercellular cross-talk requires further study.
In addition to nutrient metabolism, the dynamic properties of mitochondria—including their fusion, fission, and degradation—are vital for their optimal function and quality control [129]. Recent studies have suggested that mitochondrial dynamics and quality control mechanism mitophagy play a key role in NAFLD [130]. Several lines of evidence have revealed that miR-29a can modulate mitochondrial homeostasis by directly targeting key genes. With regard to protecting mitochondrial structural integrity, miR-29a can target voltage-dependent anion channel [131] and Bcl-2-associated X (BAX) genes [132], whose oligomerization is involved in MPT pore opening and mtDAMPs release [100,133]. The p53 upregulated modulator of apoptosis (PUMA), an activator of BAX/BAK for the induction of MPT and subsequent apoptosis, can also be targeted by miR-29a [134]. Moreover, one computational analysis revealed that miR-29a targets dynamin-related protein 1 (DRP1) [135], implying its potential role in regulating mitochondrial dynamics and mitophagy. In line with the aforementioned studies, our experimental results have shown that liver protective-miR-29a can reduce BAX expression [46]. More in-depth studies are warranted to investigate the therapeutic potential of miR-29a and shed light on the sophisticated interplay between miR-29a, mitochondrial repurposing, and inflammatory signaling.
In this regard, miR-34a/SIRT1/AMPK pathway was shown to cause mitochondrial dynamics dysfunction in mouse NASH model [136]. Another late study presented that miR-34a impair mitochondria quality control mechanism through Sirt3/FoxO3a/PINK1 signaling in an experimental mouse model of liver inflammation [137].

6. MiRNAs Involved in Lipid Metabolism of NALFD

In the context of NAFLD, dysregulated miRs critically contribute to perturb pathways for lipid metabolism, including (i)synthesis of FA, triglycerides, and cholesterol, (ii) uptake of lipid in the blood, (iii) hepatic export of lipid and (iv) lipid oxidation [14]. These aberrances could aggravate steatosis and impair cellular redox, leading to lipid peroxidation [138]. Furthermore, lipid peroxidation-produced l 4-hydroxy-trans-2-nonenal (HNE) was shown to activate proinflammatory transcription factor NF-κB [139]. In this regard, miR-122 which is the most abundant miRs in the liver was recognized as a prominent example in these metabolic processes. Overexpression of miR-122 was shown to counteract lipid accumulation in cultured hepatocytes or in the liver of NASH mouse model through several mechanisms, such as: (i) Yin Yang 1, farnesoid X receptor, and small heterodimer partner (YY1/FXR/SHP) axis [140]; (ii) hypoxia-inducible factor-1alpha, vimentin, and mitogen-activated protein kinase kinase kinase 3 (HIF-1α/vimentin/MAP3K3) axis [141]; (iii) hepatocyte nuclear factor 4α (HNF4α) pathway [142]; stearoyl-CoA desaturase gene (SCD) [143].
In addition, the key role of miR-21 in hepatic lipid metabolism has recently been highlighted [14,144]. miR-21 can target phosphatase and tensin homolog (PTEN), which prevents hepatic steatosis, and PPARα, which activates lipid oxidation. Hepatocyte-specific knockout of miR-21 in mice improved HFD-induced steatosis through upregulation of multiple miR-21-targeted pathways governing lipid metabolism [145]. In lung cancer cells, inhibition of miR-21 was shown to restrain FA uptake by down-regulating CD36 protein expression [146].
MiR-33 is intimately implicated in both cholesterol and FA metabolism. In hepatic cell lines, miR-33 targets ABCA1 and ABCG1, which are cholesterol efflux regulatory proteins, and carnitine Palmitoyltransferase 1A (CPT1A) and AMPKα [147,148], which regulate FA β-oxidation. However, the effect of miR-33 in the pathogenesis of NAFLD appears to be debatable. Horie et al. showed that deletion of miR-33 in mice results in aggravating obesity and liver fibrosis induced by HFD via targeting sterol regulatory element-binding protein 1 (SREBP1) [149]. As well, Price et al. demonstrated that abrogation of miR-33 promotes obesity and insulin resistance [150]. On the contrary, Karunakaran et al. presented therapeutic effect of miR-33 inhibitor on promoting FA oxidation and preventing atherosclerosis in mice [151].
Of particular note, the central role of miR-29a in lipid metabolism was identified by Mattis et al. Their study conducted a bias-free, hepatocyte-specific global miRNAs deficiency in mouse and combined gene/miR profiling, demonstrating that miR-29a acts to prevent lipid accumulation in the liver by targeting lipoprotein lipase (LPL) 3′UPR [152]. These evidences underscore miR-29a/LPL axis’s close involvement in the reprogramming of lipid distribution in the liver, which may account for preventing steatosis-steatohepatitis transition (Figure 1).

7. The Role of miR-29a in Fibrogenesis

Stressed hepatocyte release mtDAMPs, which leads to KC activation. Inflammatory mediators secreted by activated KC trigger activation of HSC. HSC activation consequently plays a central role for liver fibrogenesis, because these cells transdifferentiate into myofibroblasts and represent the major extracellular matrix producing cells [5,153,154]. Free cholesterol accumulation caused-lipotoxicity sensitizes HSCs to TGFβ-induced activation through TLR4 signaling in NASH mouse model [155]. Our previous work showed that overexpression of miR-29a exerts anti-fibrotic effect in BDL mouse model, and acts to reduce fibrogenesis by down-regulating COL1A1 and induce HSC apoptosis by enhancing PTEN [39]. Meanwhile, our findings revealed that miR-29a also regulates innate immune response through surpassing pattern recognition receptors TLR2/TLR4 in HSC. This effect in vivo contributes to a reduction of MyD88 and NK-kB, leading to decreased proinflammatory cytokines [45]. In NASH mouse model, we demonstrated that miR-29aTg provides protective effect through suppressing TGF-β and SMAD3 [37], two critical positive regulator of HSC activation [156]. Furthermore, we recently uncovered that anti-fibrotic effect of miR-29a is associated with inhibition of bromodomain-containing protein 4 (BRD4) in HSC [38], which represents a novel therapeutic target of liver fibrosis [157]. In view of using miR-29a as an interventional approach, Matsumoto et al. have demonstrated that administration of miR-29a can reverse liver fibrosis in CCl4− and thioacetamide-treated mice. Mechanical study revealed that miR-29 in HSC inhibits extracellular matrix production via targeting COL1A1 and FGL2, proliferation via targeting mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and platelet-derived growth factor C (PDGFC). It also acts to anti-inflammation and pro-apoptosis through repressing IL-1β and BCL-2 [48]. In addition, Knabel et al. demonstrated that administration of adeno-associated virus (AAV) serotype 8-encoded miR-29a prevents CCl4-induced liver fibrosis [158].
In contrast to miR-29a, studies with reference to miR-34a is still in dispute. MiR-29a was reported to exert detrimental effect in promoting HSC activation and liver fibrosis via targeting Sirt1 [159], while another study demonstrated that overexpression of miR-34 in HSCs ameliorated the development and progression of liver fibrosis by targeting Smad4 and regulating TGF-β1/Smad3 pathway [160]. In addition, exogenous mir-122 was shown to exerts inhibitory effect on mouse liver fibrosis and HSC activation via a mutual modulation with sterol regulatory element-binding protein-1c (SREBP-1c) [161].

8. Conclusions

NAFLD can be caused by lipid dysregulation in hepatocytes, elevated ROS, and the activation of proinflammatory mediators of KC, as well as fibrogenic pathways of activated HSC, thus leading to NASH and NASF and rendering a predisposed milieu for cirrhosis and HCC. Therefore, curative approaches focused on modulating epigenetic modification and the inhibition of metabolic damage, oxidative stress, inflammation, and fibrogenic signaling to treat NAFLD is vital but challenging. As such, the role of miR-29a is emerging because its versatile function on epigenetic activity, mitochondrial homeostasis, and immunomodulation may improve our understanding of NAFLD (Figure 1). Increasing evidence has emphasized that miR-based therapeutic tools have potential and the significance of miR-29a is emerging, paving an innovative path for the future treatment of NAFLD.

Author Contributions

All authors substantially contributed to this work. H.-Y.L. and Y.-H.H. designed the concept of the present article. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the National Health Research Institute (NHRI-EX107-10736SI), the Ministry of Science and Technology, Taiwan (106-2314-B-182A-141 -MY3; 108-2811-B-182A-509), and Chang Gung Memorial Hospital, Taiwan (CMRPG8I0941, 8I0942 and 8G1342). However, these organizations had no part in the study design, data collection and analysis, publication decisions, or preparation of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Rinella, M.E. Nonalcoholic fatty liver disease: A systematic review. JAMA 2015, 313, 2263–2273. [Google Scholar] [CrossRef] [PubMed]
  2. Tian, Y.; Yang, B.; Qiu, W.; Hao, Y.; Zhang, Z.; Yang, B.; Li, N.; Cheng, S.; Lin, Z.; Rui, Y.C.; et al. ER-residential Nogo-B accelerates NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy. Nat. Commun. 2019, 10, 3391. [Google Scholar] [CrossRef] [PubMed]
  3. El Hadi, H.; Di Vincenzo, A.; Vettor, R.; Rossato, M. Cardio-Metabolic Disorders in Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2019, 20, 2215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Lombardi, R.; Fargion, S.; Fracanzani, A.L. Brain involvement in non-alcoholic fatty liver disease (NAFLD): A systematic review. Dig. Liver Dis. 2019, 51, 1214–1222. [Google Scholar] [CrossRef] [PubMed]
  5. Lee, J.; Park, J.S.; Roh, Y.S. Molecular insights into the role of mitochondria in non-alcoholic fatty liver disease. Arch. Pharm. Res. 2019, 42, 935–946. [Google Scholar] [CrossRef] [PubMed]
  6. Leveille, M.; Estall, J.L. Mitochondrial Dysfunction in the Transition from NASH to HCC. Metabolites 2019, 9, 233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Stavast, C.J.; Erkeland, S.J. The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation. Cells 2019, 8, 1465. [Google Scholar] [CrossRef] [Green Version]
  8. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297. [Google Scholar] [CrossRef] [Green Version]
  9. Xiao, M.; Li, J.; Li, W.; Wang, Y.; Wu, F.; Xi, Y.; Zhang, L.; Ding, C.; Luo, H.; Li, Y.; et al. MicroRNAs activate gene transcription epigenetically as an enhancer trigger. RNA Biol. 2017, 14, 1326–1334. [Google Scholar] [CrossRef]
  10. Lee, I.; Ajay, S.S.; Yook, J.I.; Kim, H.S.; Hong, S.H.; Kim, N.H.; Dhanasekaran, S.M.; Chinnaiyan, A.M.; Athey, B.D. New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res. 2009, 19, 1175–1183. [Google Scholar] [CrossRef] [Green Version]
  11. Fabbri, M.; Paone, A.; Calore, F.; Galli, R.; Croce, C.M. A new role for microRNAs, as ligands of Toll-like receptors. RNA Biol. 2013, 10, 169–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Fabbri, M.; Paone, A.; Calore, F.; Galli, R.; Gaudio, E.; Santhanam, R.; Lovat, F.; Fadda, P.; Mao, C.; Nuovo, G.J.; et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl. Acad. Sci. USA 2012, 109, E2110–E2116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Das, S.; Bedja, D.; Campbell, N.; Dunkerly, B.; Chenna, V.; Maitra, A.; Steenbergen, C. miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. PLoS ONE 2014, 9, e96820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Gjorgjieva, M.; Sobolewski, C.; Dolicka, D.; Correia de Sousa, M.; Foti, M. miRNAs and NAFLD: From pathophysiology to therapy. Gut. 2019, 68, 2065–2079. [Google Scholar] [CrossRef] [PubMed]
  15. Vienberg, S.; Geiger, J.; Madsen, S.; Dalgaard, L.T. MicroRNAs in metabolism. Acta Physiol. 2017, 219, 346–361. [Google Scholar] [CrossRef] [PubMed]
  16. Huang, Y.H.; Yang, Y.L.; Wang, F.S. The Role of miR-29a in the Regulation, Function, and Signaling of Liver Fibrosis. Int. J. Mol. Sci. 2018, 19, 1889. [Google Scholar] [CrossRef] [Green Version]
  17. Kriegel, A.J.; Liu, Y.; Fang, Y.; Ding, X.; Liang, M. The miR-29 family: Genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol. Genom. 2012, 44, 237–244. [Google Scholar] [CrossRef]
  18. Muller, M.; Jakel, L.; Bruinsma, I.B.; Claassen, J.A.; Kuiperij, H.B.; Verbeek, M.M. MicroRNA-29a Is a Candidate Biomarker for Alzheimer’s Disease in Cell-Free Cerebrospinal Fluid. Mol. Neurobiol. 2016, 53, 2894–2899. [Google Scholar] [CrossRef] [Green Version]
  19. Goh, S.Y.; Chao, Y.X.; Dheen, S.T.; Tan, E.K.; Tay, S.S. Role of MicroRNAs in Parkinson’s Disease. Int. J. Mol. Sci. 2019, 20, 5649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Huang, J.; Song, G.; Yin, Z.; Fu, Z.; Ye, Z. MiR-29a and Messenger RNA Expression of Bone Turnover Markers in Canonical Wnt Pathway in Patients with Ankylosing Spondylitis. Clin. Lab. 2017, 63, 955–960. [Google Scholar] [CrossRef]
  21. Huang, Y.Q.; Cai, A.P.; Chen, J.Y.; Huang, C.; Li, J.; Feng, Y.Q. The Relationship of Plasma miR-29a and Oxidized Low Density Lipoprotein with Atherosclerosis. Cell Physiol. Biochem. 2016, 40, 1521–1528. [Google Scholar] [CrossRef] [PubMed]
  22. Zhao, Y.; Yuan, Y.; Qiu, C. Underexpression of CACNA1C Caused by Overexpression of microRNA-29a Underlies the Pathogenesis of Atrial Fibrillation. Med. Sci. Monit. 2016, 22, 2175–2181. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Afum-Adjei Awuah, A.; Ueberberg, B.; Owusu-Dabo, E.; Frempong, M.; Jacobsen, M. Dynamics of T-cell IFN-gamma and miR-29a expression during active pulmonary tuberculosis. Int. Immunol. 2014, 26, 579–582. [Google Scholar] [CrossRef] [PubMed]
  24. Jones, J.A.; Stroud, R.E.; O’Quinn, E.C.; Black, L.E.; Barth, J.L.; Elefteriades, J.A.; Bavaria, J.E.; Gorman, J.H., 3rd; Gorman, R.C.; Spinale, F.G.; et al. Selective microRNA suppression in human thoracic aneurysms: Relationship of miR-29a to aortic size and proteolytic induction. Circ. Cardiovasc. Genet. 2011, 4, 605–613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Millar, N.L.; Gilchrist, D.S.; Akbar, M.; Reilly, J.H.; Kerr, S.C.; Campbell, A.L.; Murrell, G.A.C.; Liew, F.Y.; Kurowska-Stolarska, M.; McInnes, I.B. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat. Commun. 2015, 6, 6774. [Google Scholar] [CrossRef] [Green Version]
  26. Hsu, Y.C.; Chang, P.J.; Ho, C.; Huang, Y.T.; Shih, Y.H.; Wang, C.J.; Lin, C.L. Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/beta-catenin signaling. Sci Rep. 2016, 6, 30575. [Google Scholar] [CrossRef] [Green Version]
  27. Kawashita, Y.; Jinnin, M.; Makino, T.; Kajihara, I.; Makino, K.; Honda, N.; Masuguchi, S.; Fukushima, S.; Inoue, Y.; Ihn, H. Circulating miR-29a levels in patients with scleroderma spectrum disorder. J. Derm. Sci. 2011, 61, 67–69. [Google Scholar] [CrossRef] [PubMed]
  28. Goldschmidt, I.; Thum, T.; Baumann, U. Circulating miR-21 and miR-29a as Markers of Disease Severity and Etiology in Cholestatic Pediatric Liver Disease. J. Clin. Med. 2016, 5, 28. [Google Scholar] [CrossRef] [Green Version]
  29. Jampoka, K.; Muangpaisarn, P.; Khongnomnan, K.; Treeprasertsuk, S.; Tangkijvanich, P.; Payungporn, S. Serum miR-29a and miR-122 as Potential Biomarkers for Non-Alcoholic Fatty Liver Disease (NAFLD). Microrna 2018, 7, 215–222. [Google Scholar] [CrossRef]
  30. Huang, C.; Zheng, J.M.; Cheng, Q.; Yu, K.K.; Ling, Q.X.; Chen, M.Q.; Li, N. Serum microRNA-29 levels correlate with disease progression in patients with chronic hepatitis B virus infection. J. Dig. Dis. 2014, 15, 614–621. [Google Scholar] [CrossRef]
  31. Lambrecht, J.; Verhulst, S.; Reynaert, H.; van Grunsven, L.A. The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis. Cells 2019, 8, 1003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Roderburg, C.; Urban, G.W.; Bettermann, K.; Vucur, M.; Zimmermann, H.; Schmidt, S.; Janssen, J.; Koppe, C.; Knolle, P.; Castoldi, M.; et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011, 53, 209–218. [Google Scholar] [CrossRef] [PubMed]
  33. Cho, H.J.; Kim, S.S.; Nam, J.S.; Kim, J.K.; Lee, J.H.; Kim, B.; Wang, H.J.; Kim, B.W.; Lee, J.D.; Kang, D.Y.; et al. Low levels of circulating microRNA-26a/29a as poor prognostic markers in patients with hepatocellular carcinoma who underwent curative treatment. Clin. Res. Hepatol. Gastroenterol. 2017, 41, 181–189. [Google Scholar] [CrossRef] [PubMed]
  34. Wang, J.Y.; Zhang, Q.; Wang, D.D.; Yan, W.; Sha, H.H.; Zhao, J.H.; Yang, S.J.; Zhang, H.D.; Hou, J.C.; Xu, H.Z.; et al. MiR-29a: A potential therapeutic target and promising biomarker in tumors. Biosci. Rep. 2018, 38, BSR20171265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Zhu, H.T.; Dong, Q.Z.; Sheng, Y.Y.; Wei, J.W.; Wang, G.; Zhou, H.J.; Ren, N.; Jia, H.L.; Ye, Q.H.; Qin, L.X. MicroRNA-29a-5p is a novel predictor for early recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. PLoS ONE 2012, 7, e52393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Zhu, X.C.; Dong, Q.Z.; Zhang, X.F.; Deng, B.; Jia, H.L.; Ye, Q.H.; Qin, L.X.; Wu, X.Z. microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int. J. Mol. Med. 2012, 30, 1321–1326. [Google Scholar] [CrossRef]
  37. Yang, Y.L.; Kuo, H.C.; Wang, F.S.; Huang, Y.H. MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice. Int. J. Mol. Sci. 2019, 20, 1499. [Google Scholar] [CrossRef] [Green Version]
  38. Huang, Y.H.; Kuo, H.C.; Yang, Y.L.; Wang, F.S. MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation. Int. J. Med. Sci. 2019, 16, 212–220. [Google Scholar] [CrossRef] [Green Version]
  39. Yang, Y.L.; Wang, F.S.; Li, S.C.; Tiao, M.M.; Huang, Y.H. MicroRNA-29a Alleviates Bile Duct Ligation Exacerbation of Hepatic Fibrosis in Mice through Epigenetic Control of Methyltransferases. Int. J. Mol. Sci. 2017, 18, 192. [Google Scholar] [CrossRef] [Green Version]
  40. Huang, Y.H.; Tiao, M.M.; Huang, L.T.; Chuang, J.H.; Kuo, K.C.; Yang, Y.L.; Wang, F.S. Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4. PLoS ONE 2015, 10, e0136453. [Google Scholar] [CrossRef] [Green Version]
  41. Weidle, U.H.; Schmid, D.; Birzele, F.; Brinkmann, U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genom. Proteom. 2020, 17, 1–21. [Google Scholar] [CrossRef] [PubMed]
  42. Song, G.; Tian, L.; Cheng, Y.; Liu, J.; Wang, K.; Li, S.; Li, T. Antitumor activity of sevoflurane in HCC cell line is mediated by miR-29a-induced suppression of Dnmt3a. J. Cell Biochem. 2019, 120, 18152–18161. [Google Scholar] [CrossRef] [PubMed]
  43. Chen, Q.; Yin, D.; Zhang, Y.; Yu, L.; Li, X.D.; Zhou, Z.J.; Zhou, S.L.; Gao, D.M.; Hu, J.; Jin, C.; et al. MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET-SOCS1-MMP9 signaling axis. Cell Death Dis. 2017, 8, e2906. [Google Scholar] [CrossRef] [PubMed]
  44. Lin, H.Y.; Wang, F.S.; Yang, Y.L.; Huang, Y.H. MicroRNA-29a Suppresses CD36 to Ameliorate High Fat Diet-Induced Steatohepatitis and Liver Fibrosis in Mice. Cells 2019, 8, 1298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Lin, Y.C.; Wang, F.S.; Yang, Y.L.; Chuang, Y.T.; Huang, Y.H. MicroRNA-29a mitigation of toll-like receptor 2 and 4 signaling and alleviation of obstructive jaundice-induced fibrosis in mice. Biochem. Biophys. Res. Commun. 2018, 496, 880–886. [Google Scholar] [CrossRef] [PubMed]
  46. Tiao, M.M.; Wang, F.S.; Huang, L.T.; Chuang, J.H.; Kuo, H.C.; Yang, Y.L.; Huang, Y.H. MicroRNA-29a protects against acute liver injury in a mouse model of obstructive jaundice via inhibition of the extrinsic apoptosis pathway. Apoptosis 2014, 19, 30–41. [Google Scholar] [CrossRef]
  47. Ma, J.H.; Bu, X.; Wang, J.J.; Xie, Y.X. MicroRNA-29-3p Regulates Hepatocellular Carcinoma Progression Through NF-kappaB Pathway. Clin. Lab. 2019, 65. [Google Scholar] [CrossRef]
  48. Matsumoto, Y.; Itami, S.; Kuroda, M.; Yoshizato, K.; Kawada, N.; Murakami, Y. MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice. Mol. Ther. 2016, 24, 1848–1859. [Google Scholar] [CrossRef] [Green Version]
  49. Xuan, J.; Guo, S.L.; Huang, A.; Xu, H.B.; Shao, M.; Yang, Y.; Wen, W. MiR-29a and miR-652 Attenuate Liver Fibrosis by Inhibiting the Differentiation of CD4+ T Cells. Cell Struct. Funct. 2017, 42, 95–103. [Google Scholar] [CrossRef] [Green Version]
  50. Song, S.; Sun, K.; Dong, J.; Zhao, Y.; Liu, F.; Liu, H.; Sha, Z.; Mao, J.; Ding, G.; Guo, W.; et al. microRNA-29a regulates liver tumor-initiating cells expansion via Bcl-2 pathway. Exp. Cell Res. 2019, 387. [Google Scholar] [CrossRef]
  51. Huang, Y.H.; Yang, Y.L.; Huang, F.C.; Tiao, M.M.; Lin, Y.C.; Tsai, M.H.; Wang, F.S. MicroRNA-29a mitigation of endoplasmic reticulum and autophagy aberrance counteracts in obstructive jaundice-induced fibrosis in mice. Exp. Biol Med. (Maywood) 2018, 243, 13–21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Xiong, Y.; Fang, J.H.; Yun, J.P.; Yang, J.; Zhang, Y.; Jia, W.H.; Zhuang, S.M. Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 2010, 51, 836–845. [Google Scholar] [CrossRef] [PubMed]
  53. Li, S.C.; Wang, F.S.; Yang, Y.L.; Tiao, M.M.; Chuang, J.H.; Huang, Y.H. Microarray Study of Pathway Analysis Expression Profile Associated with MicroRNA-29a with Regard to Murine Cholestatic Liver Injuries. Int. J. Mol. Sci. 2016, 17, 324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Zhu, L.R.; Feng, J.L.; Liu, X.J.; Wang, J.M. LncRNA HULC promots HCC growth by downregulating miR-29. Zhonghua Zhong Liu Za Zhi 2019, 41, 659–666. [Google Scholar] [PubMed]
  55. Zhang, Y.; Yang, L.; Wang, S.; Liu, Z.; Xiu, M. MiR-29a suppresses cell proliferation by targeting SIRT1 in hepatocellular carcinoma. Cancer Biomark. 2018, 22, 151–159. [Google Scholar] [CrossRef] [PubMed]
  56. Kong, G.; Zhang, J.; Zhang, S.; Shan, C.; Ye, L.; Zhang, X. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PLoS ONE 2011, 6, e19518. [Google Scholar] [CrossRef] [PubMed]
  57. Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75, 843–854. [Google Scholar] [CrossRef]
  58. Krutzfeldt, J.; Rajewsky, N.; Braich, R.; Rajeev, K.G.; Tuschl, T.; Manoharan, M.; Stoffel, M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005, 438, 685–689. [Google Scholar] [CrossRef]
  59. Pirola, C.J.; Fernandez Gianotti, T.; Castano, G.O.; Mallardi, P.; San Martino, J.; Mora Gonzalez Lopez Ledesma, M.; Flichman, D.; Mirshahi, F.; Sanyal, A.J.; Sookoian, S. Circulating microRNA signature in non-alcoholic fatty liver disease: From serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015, 64, 800–812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Becker, P.P.; Rau, M.; Schmitt, J.; Malsch, C.; Hammer, C.; Bantel, H.; Mullhaupt, B.; Geier, A. Performance of Serum microRNAs -122, -192 and -21 as Biomarkers in Patients with Non-Alcoholic Steatohepatitis. PLoS ONE 2015, 10, e0142661. [Google Scholar] [CrossRef]
  61. Cermelli, S.; Ruggieri, A.; Marrero, J.A.; Ioannou, G.N.; Beretta, L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE 2011, 6, e23937. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Auguet, T.; Aragones, G.; Berlanga, A.; Guiu-Jurado, E.; Marti, A.; Martinez, S.; Sabench, F.; Hernandez, M.; Aguilar, C.; Sirvent, J.J.; et al. miR33a/miR33b* and miR122 as Possible Contributors to Hepatic Lipid Metabolism in Obese Women with Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2016, 17, 1620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Liu, X.L.; Pan, Q.; Zhang, R.N.; Shen, F.; Yan, S.Y.; Sun, C.; Xu, Z.J.; Chen, Y.W.; Fan, J.G. Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population. World J. Gastroenterol 2016, 22, 9844–9852. [Google Scholar] [CrossRef] [PubMed]
  64. Yamada, H.; Suzuki, K.; Ichino, N.; Ando, Y.; Sawada, A.; Osakabe, K.; Sugimoto, K.; Ohashi, K.; Teradaira, R.; Inoue, T.; et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin. Chim. Acta 2013, 424, 99–103. [Google Scholar] [CrossRef] [PubMed]
  65. Ogawa, T.; Enomoto, M.; Fujii, H.; Sekiya, Y.; Yoshizato, K.; Ikeda, K.; Kawada, N. MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut 2012, 61, 1600–1609. [Google Scholar] [CrossRef] [PubMed]
  66. Jiang, C.; Liu, X.; Wang, M.; Lv, G.; Wang, G. High Blood miR-802 Is Associated With Poor Prognosis in HCC Patients by Regulating DNA Damage Response 1 (REDD1)-Mediated Function of T Cells. Oncol. Res. 2019, 27, 1025–1034. [Google Scholar] [CrossRef] [PubMed]
  67. Xue, X.; Zhao, Y.; Wang, X.; Qin, L.; Hu, R. Development and validation of serum exosomal microRNAs as diagnostic and prognostic biomarkers for hepatocellular carcinoma. J. Cell Biochem. 2019, 120, 135–142. [Google Scholar] [CrossRef] [Green Version]
  68. Kim, S.S.; Cho, H.J.; Nam, J.S.; Kim, H.J.; Kang, D.R.; Won, J.H.; Kim, J.; Kim, J.K.; Lee, J.H.; Kim, B.H.; et al. Plasma MicroRNA-21, 26a, and 29a-3p as Predictive Markers for Treatment Response Following Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma. J. Korean Med. Sci. 2018, 33, e6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Zhang, Z.; Shen, S. Combined low miRNA-29s is an independent risk factor in predicting prognosis of patients with hepatocellular carcinoma after hepatectomy: A Chinese population-based study. Medicine (Baltim.) 2017, 96, e8795. [Google Scholar] [CrossRef]
  70. Zhu, H.T.; Hasan, A.M.; Liu, R.B.; Zhang, Z.C.; Zhang, X.; Wang, J.; Wang, H.Y.; Wang, F.; Shao, J.Y. Serum microRNA profiles as prognostic biomarkers for HBV-positive hepatocellular carcinoma. Oncotarget 2016, 7, 45637–45648. [Google Scholar] [CrossRef] [Green Version]
  71. Eguchi, A.; Lazaro, R.G.; Wang, J.; Kim, J.; Povero, D.; Willliams, B.; Ho, S.B.; Starkel, P.; Schnabl, B.; Ohno-Machado, L.; et al. Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 2017, 65, 475–490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Lopez-Riera, M.; Conde, I.; Tolosa, L.; Zaragoza, A.; Castell, J.V.; Gomez-Lechon, M.J.; Jover, R. New microRNA Biomarkers for Drug-Induced Steatosis and Their Potential to Predict the Contribution of Drugs to Non-alcoholic Fatty Liver Disease. Front. Pharm. 2017, 8, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Jia, N.; Lin, X.; Ma, S.; Ge, S.; Mu, S.; Yang, C.; Shi, S.; Gao, L.; Xu, J.; Bo, T.; et al. Amelioration of hepatic steatosis is associated with modulation of gut microbiota and suppression of hepatic miR-34a in Gynostemma pentaphylla (Thunb.) Makino treated mice. Nutr. Metab. (Lond.) 2018, 15, 86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Liu, J.; Xiao, Y.; Wu, X.; Jiang, L.; Yang, S.; Ding, Z.; Fang, Z.; Hua, H.; Kirby, M.S.; Shou, J. A circulating microRNA signature as noninvasive diagnostic and prognostic biomarkers for nonalcoholic steatohepatitis. Bmc. Genom. 2018, 19, 188. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Liu, M.X.; Gao, M.; Li, C.Z.; Yu, C.Z.; Yan, H.; Peng, C.; Li, Y.; Li, C.G.; Ma, Z.L.; Zhao, Y.; et al. Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis. Acta. Pharm. Sin. 2017, 38, 660–671. [Google Scholar] [CrossRef] [PubMed]
  76. Oses, M.; Margareto Sanchez, J.; Portillo, M.P.; Aguilera, C.M.; Labayen, I. Circulating miRNAs as Biomarkers of Obesity and Obesity-Associated Comorbidities in Children and Adolescents: A Systematic Review. Nutrients 2019, 11, 2890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Joven, J.; Espinel, E.; Rull, A.; Aragones, G.; Rodriguez-Gallego, E.; Camps, J.; Micol, V.; Herranz-Lopez, M.; Menendez, J.A.; Borras, I.; et al. Plant-derived polyphenols regulate expression of miRNA paralogs miR-103/107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipidemic mice. Biochim. Biophys. Acta 2012, 1820, 894–899. [Google Scholar] [CrossRef] [PubMed]
  78. Mehta, R.; Otgonsuren, M.; Younoszai, Z.; Allawi, H.; Raybuck, B.; Younossi, Z. Circulating miRNA in patients with non-alcoholic fatty liver disease and coronary artery disease. BMJ Open Gastroenterol. 2016, 3, e000096. [Google Scholar] [CrossRef]
  79. Celikbilek, M.; Baskol, M.; Taheri, S.; Deniz, K.; Dogan, S.; Zararsiz, G.; Gursoy, S.; Guven, K.; Ozbakir, O. Circulating microRNAs in patients with non-alcoholic fatty liver disease. World J. Hepatol 2014, 6, 613–620. [Google Scholar] [CrossRef] [PubMed]
  80. Babu, K.R.; Muckenthaler, M.U. miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma. Sci. Rep. 2019, 9, 1518. [Google Scholar] [CrossRef] [PubMed]
  81. Long, X.R.; He, Y.; Huang, C.; Li, J. MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in hepatocellular carcinogenesis. Int. J. Oncol. 2014, 44, 1915–1922. [Google Scholar] [CrossRef] [PubMed]
  82. Huang, R.; Duan, X.; Liu, X.; Cao, H.; Wang, Y.; Fan, J.; Wang, B. Upregulation of miR-181a impairs lipid metabolism by targeting PPARalpha expression in nonalcoholic fatty liver disease. Biochem. Biophys. Res. Commun. 2019, 508, 1252–1258. [Google Scholar] [CrossRef] [PubMed]
  83. Du, X.; Yang, Y.; Xu, C.; Peng, Z.; Zhang, M.; Lei, L.; Gao, W.; Dong, Y.; Shi, Z.; Sun, X.; et al. Upregulation of miR-181a impairs hepatic glucose and lipid homeostasis. Oncotarget 2017, 8, 91362–91378. [Google Scholar] [CrossRef]
  84. Tryndyak, V.P.; Latendresse, J.R.; Montgomery, B.; Ross, S.A.; Beland, F.A.; Rusyn, I.; Pogribny, I.P. Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet. Toxicol. Appl. Pharm. 2012, 262, 52–59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Dongiovanni, P.; Meroni, M.; Longo, M.; Fargion, S.; Fracanzani, A.L. miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis. Int. J. Mol. Sci 2018, 19, 3966. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Portela, A.; Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 2010, 28, 1057–1068. [Google Scholar] [CrossRef] [PubMed]
  87. Kanherkar, R.R.; Bhatia-Dey, N.; Csoka, A.B. Epigenetics across the human lifespan. Front. Cell Dev. Biol. 2014, 2, 49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Lind, M.I.; Spagopoulou, F. Evolutionary consequences of epigenetic inheritance. Hered. (Edinb) 2018, 121, 205–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Chen, X.; Li, W.X.; Chen, Y.; Li, X.F.; Li, H.D.; Huang, H.M.; Bu, F.T.; Pan, X.Y.; Yang, Y.; Huang, C.; et al. Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis. Cell Death Dis. 2018, 9, 1021. [Google Scholar] [CrossRef]
  90. Sheen-Chen, S.M.; Lin, C.R.; Chen, K.H.; Yang, C.H.; Lee, C.T.; Huang, H.W.; Huang, C.Y. Epigenetic histone methylation regulates transforming growth factor beta-1 expression following bile duct ligation in rats. J. Gastroenterol 2014, 49, 1285–1297. [Google Scholar] [CrossRef]
  91. Perugorria, M.J.; Wilson, C.L.; Zeybel, M.; Walsh, M.; Amin, S.; Robinson, S.; White, S.A.; Burt, A.D.; Oakley, F.; Tsukamoto, H.; et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 2012, 56, 1129–1139. [Google Scholar] [CrossRef] [PubMed]
  92. Mannaerts, I.; Eysackers, N.; Onyema, O.O.; Van Beneden, K.; Valente, S.; Mai, A.; Odenthal, M.; van Grunsven, L.A. Class II HDAC inhibition hampers hepatic stellate cell activation by induction of microRNA-29. PLoS ONE 2013, 8, e55786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Van Beneden, K.; Mannaerts, I.; Pauwels, M.; Van den Branden, C.; van Grunsven, L.A. HDAC inhibitors in experimental liver and kidney fibrosis. Fibrogenesis Tissue Repair 2013, 6, 1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Bahat, A.; Gross, A. Mitochondrial plasticity in cell fate regulation. J. Biol. Chem. 2019, 294, 13852–13863. [Google Scholar] [CrossRef] [Green Version]
  95. Yin, X.; Zheng, F.; Pan, Q.; Zhang, S.; Yu, D.; Xu, Z.; Li, H. Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening. J. Mol. Endocrinol. 2015, 55, 169–181. [Google Scholar] [CrossRef] [Green Version]
  96. Mantena, S.K.; Vaughn, D.P.; Andringa, K.K.; Eccleston, H.B.; King, A.L.; Abrams, G.A.; Doeller, J.E.; Kraus, D.W.; Darley-Usmar, V.M.; Bailey, S.M. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem. J. 2009, 417, 183–193. [Google Scholar] [CrossRef] [Green Version]
  97. Fan, W.X.; Wen, X.L.; Xiao, H.; Yang, Q.P.; Liang, Z. MicroRNA-29a enhances autophagy in podocytes as a protective mechanism against high glucose-induced apoptosis by targeting heme oxygenase-1. Eur. Rev. Med. Pharm. Sci. 2018, 22, 8909–8917. [Google Scholar]
  98. Vringer, E.; Tait, S.W.G. Mitochondria and Inflammation: Cell Death Heats Up. Front. Cell Dev. Biol. 2019, 7, 100. [Google Scholar] [CrossRef]
  99. Zhong, Z.; Liang, S.; Sanchez-Lopez, E.; He, F.; Shalapour, S.; Lin, X.J.; Wong, J.; Ding, S.; Seki, E.; Schnabl, B.; et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 2018, 560, 198–203. [Google Scholar] [CrossRef] [PubMed]
  100. Dhir, A.; Dhir, S.; Borowski, L.S.; Jimenez, L.; Teitell, M.; Rotig, A.; Crow, Y.J.; Rice, G.I.; Duffy, D.; Tamby, C.; et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 2018, 560, 238–242. [Google Scholar] [CrossRef] [PubMed]
  101. Marques, P.E.; Oliveira, A.G.; Pereira, R.V.; David, B.A.; Gomides, L.F.; Saraiva, A.M.; Pires, D.A.; Novaes, J.T.; Patricio, D.O.; Cisalpino, D.; et al. Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice. Hepatology 2015, 61, 348–360. [Google Scholar] [CrossRef] [PubMed]
  102. Garcia-Martinez, I.; Santoro, N.; Chen, Y.; Hoque, R.; Ouyang, X.; Caprio, S.; Shlomchik, M.J.; Coffman, R.L.; Candia, A.; Mehal, W.Z. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Investig. 2016, 126, 859–864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Murgia, M.; Giorgi, C.; Pinton, P.; Rizzuto, R. Controlling metabolism and cell death: At the heart of mitochondrial calcium signalling. J. Mol. Cell Cardiol. 2009, 46, 781–788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2009, 417, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Chaung, W.W.; Wu, R.; Ji, Y.; Dong, W.; Wang, P. Mitochondrial transcription factor A is a proinflammatory mediator in hemorrhagic shock. Int. J. Mol. Med. 2012, 30, 199–203. [Google Scholar]
  106. Lee, J.H.; Shim, Y.R.; Seo, W.; Kim, M.H.; Choi, W.M.; Kim, H.H.; Kim, Y.E.; Yang, K.; Ryu, T.; Jeong, J.M.; et al. Mitochondrial double-stranded RNA in exosome promotes interleukin-17 production through toll-like receptor 3 in alcoholic liver injury. Hepatology 2019. [Google Scholar] [CrossRef]
  107. Zhang, R.; Wang, X.; Qu, J.H.; Liu, B.; Zhang, P.; Zhang, T.; Fan, P.C.; Wang, X.M.; Xiao, G.Y.; Su, Y.; et al. Caloric Restriction Induces MicroRNAs to Improve Mitochondrial Proteostasis. iScience 2019, 17, 155–166. [Google Scholar] [CrossRef] [Green Version]
  108. Ding, J.; Li, M.; Wan, X.; Jin, X.; Chen, S.; Yu, C.; Li, Y. Effect of miR-34a in regulating steatosis by targeting PPARalpha expression in nonalcoholic fatty liver disease. Sci Rep. 2015, 5, 13729. [Google Scholar] [CrossRef] [Green Version]
  109. Loyer, X.; Paradis, V.; Henique, C.; Vion, A.C.; Colnot, N.; Guerin, C.L.; Devue, C.; On, S.; Scetbun, J.; Romain, M.; et al. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression. Gut. 2016, 65, 1882–1894. [Google Scholar] [CrossRef] [Green Version]
  110. Rector, R.S.; Thyfault, J.P.; Uptergrove, G.M.; Morris, E.M.; Naples, S.P.; Borengasser, S.J.; Mikus, C.R.; Laye, M.J.; Laughlin, M.H.; Booth, F.W.; et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J. Hepatol. 2010, 52, 727–736. [Google Scholar] [CrossRef] [Green Version]
  111. Grattagliano, I.; de Bari, O.; Bernardo, T.C.; Oliveira, P.J.; Wang, D.Q.; Portincasa, P. Role of mitochondria in nonalcoholic fatty liver disease--from origin to propagation. Clin. Biochem. 2012, 45, 610–618. [Google Scholar] [CrossRef] [PubMed]
  112. Sunny, N.E.; Bril, F.; Cusi, K. Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies. Trends Endocrinol. Metab. 2017, 28, 250–260. [Google Scholar] [CrossRef] [PubMed]
  113. Degli Esposti, D.; Hamelin, J.; Bosselut, N.; Saffroy, R.; Sebagh, M.; Pommier, A.; Martel, C.; Lemoine, A. Mitochondrial roles and cytoprotection in chronic liver injury. Biochem. Res. Int. 2012, 2012, 387626. [Google Scholar] [CrossRef] [PubMed]
  114. Zhong, S.; Zhao, L.; Wang, Y.; Zhang, C.; Liu, J.; Wang, P.; Zhou, W.; Yang, P.; Varghese, Z.; Moorhead, J.F.; et al. Cluster of Differentiation 36 Deficiency Aggravates Macrophage Infiltration and Hepatic Inflammation by Upregulating Monocyte Chemotactic Protein-1 Expression of Hepatocytes Through Histone Deacetylase 2-Dependent Pathway. Antioxid. Redox Signal. 2017, 27, 201–214. [Google Scholar] [CrossRef] [PubMed]
  115. Zhou, J.; Febbraio, M.; Wada, T.; Zhai, Y.; Kuruba, R.; He, J.; Lee, J.H.; Khadem, S.; Ren, S.; Li, S.; et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008, 134, 556–567. [Google Scholar] [CrossRef] [PubMed]
  116. Zhan, Z.; Ren, H.; Peng, M.L. Role of CD36 in nonalcoholic fatty liver disease. Zhonghua Gan Zang Bing Za Zhi 2017, 25, 953–956. [Google Scholar]
  117. Wang, Y.; Koch, M.; di Giuseppe, R.; Evans, K.; Borggrefe, J.; Nothlings, U.; Handberg, A.; Jensen, M.K.; Lieb, W. Associations of plasma CD36 and body fat distribution. J. Clin. Endocrinol. Metab. 2019, Jc.2019-00368. [Google Scholar] [CrossRef]
  118. Li, Y.; Yang, P.; Zhao, L.; Chen, Y.; Zhang, X.; Zeng, S.; Wei, L.; Varghese, Z.; Moorhead, J.F.; Chen, Y.; et al. CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway. J. Lipid Res. 2019, 60, 844–855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Wilson, C.G.; Tran, J.L.; Erion, D.M.; Vera, N.B.; Febbraio, M.; Weiss, E.J. Hepatocyte-Specific Disruption of CD36 Attenuates Fatty Liver and Improves Insulin Sensitivity in HFD-Fed Mice. Endocrinology 2016, 157, 570–585. [Google Scholar] [CrossRef] [Green Version]
  120. Begriche, K.; Massart, J.; Robin, M.A.; Bonnet, F.; Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 2013, 58, 1497–1507. [Google Scholar] [CrossRef]
  121. Reddy, J.K.; Rao, M.S. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Gastrointest Liver Physiol. 2006, 290, G852–G858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Chen, Y.; Yang, M.; Huang, W.; Chen, W.; Zhao, Y.; Schulte, M.L.; Volberding, P.J.; Gerbec, Z.; Zimmermann, M.T.; Zeighami, A.; et al. Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses. Circ. Res. 2019, 125, 1087–1102. [Google Scholar] [CrossRef] [PubMed]
  123. Ipsen, D.H.; Lykkesfeldt, J.; Tveden-Nyborg, P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol. Life Sci. 2018, 75, 3313–3327. [Google Scholar] [CrossRef] [Green Version]
  124. McGettigan, B.; McMahan, R.; Orlicky, D.; Burchill, M.; Danhorn, T.; Francis, P.; Cheng, L.L.; Golden-Mason, L.; Jakubzick, C.V.; Rosen, H.R. Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages. Hepatology 2019, 70, 67–83. [Google Scholar] [CrossRef] [PubMed]
  125. Ho, C.M.; Ho, S.L.; Jeng, Y.M.; Lai, Y.S.; Chen, Y.H.; Lu, S.C.; Chen, H.L.; Chang, P.Y.; Hu, R.H.; Lee, P.H. Accumulation of free cholesterol and oxidized low-density lipoprotein is associated with portal inflammation and fibrosis in nonalcoholic fatty liver disease. J. Inflamm. (Lond) 2019, 16, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Houben, T.; Oligschlaeger, Y.; Bitorina, A.V.; Hendrikx, T.; Walenbergh, S.M.A.; Lenders, M.H.; Gijbels, M.J.J.; Verheyen, F.; Lutjohann, D.; Hofker, M.H.; et al. Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation. Sci. Rep. 2017, 7, 12550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Kawanishi, N.; Mizokami, T.; Yada, K.; Suzuki, K. Exercise training suppresses scavenger receptor CD36 expression in kupffer cells of nonalcoholic steatohepatitis model mice. Physiol. Rep. 2018, 6, e13902. [Google Scholar] [CrossRef] [PubMed]
  128. Wu, R.W.; Lian, W.S.; Chen, Y.S.; Kuo, C.W.; Ke, H.C.; Hsieh, C.K.; Wang, S.Y.; Ko, J.Y.; Wang, F.S. MicroRNA-29a Counteracts Glucocorticoid Induction of Bone Loss through Repressing TNFSF13b, Modulation of Osteoclastogenesis. Int. J. Mol. Sci. 2019, 20, 5141. [Google Scholar] [CrossRef] [Green Version]
  129. Liu, Y.; Merrill, R.A.; Strack, S. A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease. Cells 2020, 9, 298. [Google Scholar] [CrossRef] [Green Version]
  130. Mansouri, A.; Gattolliat, C.H.; Asselah, T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology 2018, 155, 629–647. [Google Scholar] [CrossRef] [Green Version]
  131. Bargaje, R.; Gupta, S.; Sarkeshik, A.; Park, R.; Xu, T.; Sarkar, M.; Halimani, M.; Roy, S.S.; Yates, J.; Pillai, B. Identification of novel targets for miR-29a using miRNA proteomics. PLoS ONE 2012, 7, e43243. [Google Scholar] [CrossRef] [PubMed]
  132. Zhang, L.; Zhang, J.; Tong, Q.; Wang, G.; Dong, H.; Wang, Z.; Sun, Q.; Wu, H. Reduction of miR-29a-3p induced cardiac ischemia reperfusion injury in mice via targeting Bax. Exp. Med. 2019, 18, 1729–1737. [Google Scholar] [CrossRef] [PubMed]
  133. Betaneli, V.; Petrov, E.P.; Schwille, P. The role of lipids in VDAC oligomerization. Biophys. J. 2012, 102, 523–531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Ouyang, Y.B.; Xu, L.; Lu, Y.; Sun, X.; Yue, S.; Xiong, X.X.; Giffard, R.G. Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia 2013, 61, 1784–1794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Jan, M.I.; Khan, R.A.; Malik, A.; Ali, T.; Bilal, M.; Bo, L.; Sajid, A.; Urehman, N.; Waseem, N.; Nawab, J.; et al. Data of expression status of miR- 29a and its putative target mitochondrial apoptosis regulatory gene DRP1 upon miR-15a and miR-214 inhibition. Data Brief. 2018, 16, 1000–1004. [Google Scholar] [CrossRef]
  136. Simao, A.L.; Afonso, M.B.; Rodrigues, P.M.; Gama-Carvalho, M.; Machado, M.V.; Cortez-Pinto, H.; Rodrigues, C.M.P.; Castro, R.E. Skeletal muscle miR-34a/SIRT1:AMPK axis is activated in experimental and human non-alcoholic steatohepatitis. J. Mol. Med. (Berl) 2019, 97, 1113–1126. [Google Scholar] [CrossRef]
  137. Chen, F.; Feng, L.; Zheng, Y.L.; Lu, J.; Fan, S.H.; Shan, Q.; Zheng, G.H.; Wang, Y.J.; Wu, D.M.; Li, M.Q.; et al. 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47) induces mitochondrial dysfunction and related liver injury via eliciting miR-34a-5p-mediated mitophagy impairment. Environ. Pollut. 2020, 258, 113693. [Google Scholar] [CrossRef]
  138. Lebeaupin, C.; Vallee, D.; Hazari, Y.; Hetz, C.; Chevet, E.; Bailly-Maitre, B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 2018, 69, 927–947. [Google Scholar] [CrossRef]
  139. Yadav, U.C.; Ramana, K.V. Regulation of NF-kappaB-induced inflammatory signaling by lipid peroxidation-derived aldehydes. Oxid Med. Cell Longev. 2013, 2013, 690545. [Google Scholar] [CrossRef] [Green Version]
  140. Wu, G.Y.; Rui, C.; Chen, J.Q.; Sho, E.; Zhan, S.S.; Yuan, X.W.; Ding, Y.T. MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1. Cell Physiol. Biochem. 2017, 44, 1651–1664. [Google Scholar] [CrossRef]
  141. Csak, T.; Bala, S.; Lippai, D.; Satishchandran, A.; Catalano, D.; Kodys, K.; Szabo, G. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int. 2015, 35, 532–541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Li, Z.Y.; Xi, Y.; Zhu, W.N.; Zeng, C.; Zhang, Z.Q.; Guo, Z.C.; Hao, D.L.; Liu, G.; Feng, L.; Chen, H.Z.; et al. Positive regulation of hepatic miR-122 expression by HNF4alpha. J. Hepatol. 2011, 55, 602–611. [Google Scholar] [CrossRef] [PubMed]
  143. Qiang, J.; Tao, Y.F.; Bao, J.W.; Chen, J.; Li, H.X.; He, J.; Xu, P. High Fat Diet-Induced miR-122 Regulates Lipid Metabolism and Fat Deposition in Genetically Improved Farmed Tilapia (GIFT, Oreochromis niloticus) Liver. Front. Physiol. 2018, 9, 1422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Rodrigues, P.M.; Rodrigues, C.M.P.; Castro, R.E. Modulation of liver steatosis by miR-21/PPARalpha. Cell Death Discov. 2018, 4, 9. [Google Scholar] [CrossRef] [PubMed]
  145. Calo, N.; Ramadori, P.; Sobolewski, C.; Romero, Y.; Maeder, C.; Fournier, M.; Rantakari, P.; Zhang, F.P.; Poutanen, M.; Dufour, J.F.; et al. Stress-activated miR-21/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption. Gut 2016, 65, 1871–1881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Ni, K.; Wang, D.; Xu, H.; Mei, F.; Wu, C.; Liu, Z.; Zhou, B. miR-21 promotes non-small cell lung cancer cells growth by regulating fatty acid metabolism. Cancer Cell Int. 2019, 19, 219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Davalos, A.; Goedeke, L.; Smibert, P.; Ramirez, C.M.; Warrier, N.P.; Andreo, U.; Cirera-Salinas, D.; Rayner, K.; Suresh, U.; Pastor-Pareja, J.C.; et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc. Natl. Acad. Sci. USA 2011, 108, 9232–9237. [Google Scholar] [CrossRef] [Green Version]
  148. Rayner, K.J.; Suarez, Y.; Davalos, A.; Parathath, S.; Fitzgerald, M.L.; Tamehiro, N.; Fisher, E.A.; Moore, K.J.; Fernandez-Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 2010, 328, 1570–1573. [Google Scholar] [CrossRef] [Green Version]
  149. Horie, T.; Nishino, T.; Baba, O.; Kuwabara, Y.; Nakao, T.; Nishiga, M.; Usami, S.; Izuhara, M.; Sowa, N.; Yahagi, N.; et al. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. Nat. Commun. 2013, 4, 2883. [Google Scholar] [CrossRef] [Green Version]
  150. Price, N.L.; Rotllan, N.; Canfran-Duque, A.; Zhang, X.; Pati, P.; Arias, N.; Moen, J.; Mayr, M.; Ford, D.A.; Baldan, A.; et al. Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis. Cell Rep. 2017, 21, 1317–1330. [Google Scholar] [CrossRef] [Green Version]
  151. Karunakaran, D.; Richards, L.; Geoffrion, M.; Barrette, D.; Gotfrit, R.J.; Harper, M.E.; Rayner, K.J. Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity. Arter. Thromb. Vasc. Biol. 2015, 35, 2536–2543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Mattis, A.N.; Song, G.; Hitchner, K.; Kim, R.Y.; Lee, A.Y.; Sharma, A.D.; Malato, Y.; McManus, M.T.; Esau, C.C.; Koller, E.; et al. A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver. Hepatology 2015, 61, 141–152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. da Silva Meirelles, L.; Marson, R.F.; Solari, M.I.G.; Nardi, N.B. Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair. Cells 2020, 9, 188. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Tsuchida, T.; Friedman, S.L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol Hepatol. 2017, 14, 397–411. [Google Scholar] [CrossRef] [PubMed]
  155. Tomita, K.; Teratani, T.; Suzuki, T.; Shimizu, M.; Sato, H.; Narimatsu, K.; Okada, Y.; Kurihara, C.; Irie, R.; Yokoyama, H.; et al. Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 2014, 59, 154–169. [Google Scholar] [CrossRef] [PubMed]
  156. Yoshida, K.; Murata, M.; Yamaguchi, T.; Matsuzaki, K. TGF-beta/Smad signaling during hepatic fibro-carcinogenesis (review). Int. J. Oncol. 2014, 45, 1363–1371. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Ding, N.; Hah, N.; Yu, R.T.; Sherman, M.H.; Benner, C.; Leblanc, M.; He, M.; Liddle, C.; Downes, M.; Evans, R.M. BRD4 is a novel therapeutic target for liver fibrosis. Proc. Natl. Acad. Sci. USA 2015, 112, 15713–15718. [Google Scholar] [CrossRef] [Green Version]
  158. Knabel, M.K.; Ramachandran, K.; Karhadkar, S.; Hwang, H.W.; Creamer, T.J.; Chivukula, R.R.; Sheikh, F.; Clark, K.R.; Torbenson, M.; Montgomery, R.A.; et al. Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice. PLoS ONE 2015, 10, e0124411. [Google Scholar] [CrossRef] [Green Version]
  159. Liu, Q.; Zhang, Y.; Yang, S.; Wu, Y.; Wang, J.; Yu, W.; Liu, Y. 1-deficient mice are resistant to thioacetamide-induced hepatic fibrosis: PU.1 finely regulates Sirt1 expression via transcriptional promotion of miR-34a and miR-29c in hepatic stellate cells. Biosci. Rep. 2017, 37, BSR20170926. [Google Scholar] [CrossRef] [Green Version]
  160. Feili, X.; Wu, S.; Ye, W.; Tu, J.; Lou, L. MicroRNA-34a-5p inhibits liver fibrosis by regulating TGF-beta1/Smad3 pathway in hepatic stellate cells. Cell Biol. Int. 2018, 42, 1370–1376. [Google Scholar] [CrossRef]
  161. Zhai, X.; Cheng, F.; Ji, L.; Zhu, X.; Cao, Q.; Zhang, Y.; Jia, X.; Zhou, Q.; Guan, W.; Zhou, Y. Leptin reduces microRNA-122 level in hepatic stellate cells in vitro and in vivo. Mol. Immunol. 2017, 92, 68–75. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Role of miR-29a on modulating hepatic mtDAMPs release, lipid metabolism, inflammation, and fibrogenic signaling in the pathogenesis of NAFLD. Underlined genes represent miR-29a targets. BAX, Bcl-2-associated X protein; FGL2, fibrinogen-like 2; LPL, lipoprotein lipase; mtDAMPs, mitochondrial danger-associated molecular patterns; mtDNA, mitochondrial DNA; mtdsRNA, mitochondrial double-stranded RNA; NFP, N-formyl peptides; PRRs, pattern recognition receptors; NLRP3, NOD-like receptor family pyrin domain containing 3; TLR9, toll-like receptor 9.
Figure 1. Role of miR-29a on modulating hepatic mtDAMPs release, lipid metabolism, inflammation, and fibrogenic signaling in the pathogenesis of NAFLD. Underlined genes represent miR-29a targets. BAX, Bcl-2-associated X protein; FGL2, fibrinogen-like 2; LPL, lipoprotein lipase; mtDAMPs, mitochondrial danger-associated molecular patterns; mtDNA, mitochondrial DNA; mtdsRNA, mitochondrial double-stranded RNA; NFP, N-formyl peptides; PRRs, pattern recognition receptors; NLRP3, NOD-like receptor family pyrin domain containing 3; TLR9, toll-like receptor 9.
Cells 09 01041 g001
Table 1. Pleiotropic Role of miR-29a in in Liver Disease.
Table 1. Pleiotropic Role of miR-29a in in Liver Disease.
Affected PathwayDisease ModelmiR-29a TargetsReferences
EpigeneticsNASH, liver fibrosis, HCCDNMT3b, HDAC4, DNMT3a, TET1[37,38,39,40,41,42,43]
Oxidative stress/InflammatoryNASH, liver fibrosis, HCCCD36, DNMT3b, HDAC4, ARRB1, PTEN[37,40,44,45,46,47,48,49]
Apoptosisliver fibrosis, HCCCOL1A1, FGL2, MAP4K4, PDGFC, BCL-2, DNMT3a, MCL-1[42,46,48,50,51,52]
AutophagyNASH, liver fibrosis, HCCDNMT3b, SPARC[36,37,51]
Epithelial-mesenchymal transitionNASH, liver fibrosisCOL1A1, FGL2, MAP4K4, PDGFC[37,39,40,44,45,46,48,51,53]
Cell cycleHCCSIRT1; SPARC; HULC, TET1, TET2, TET3[36,41,43,54,55]
Cell migrationHCCCLDN1, TET1, TET2, TET3, PTEN[41,43,56]
Table 3. Clinical Relevance of miR-29a in the Diagnosis of Liver Disease.
Table 3. Clinical Relevance of miR-29a in the Diagnosis of Liver Disease.
SourceExpressionClinical RelevanceReference
PlasmaDownBiomarker implicated in miRFIB scoring algorithm for diagnosis of liver fibrosis [31]
SerumDownReduced miR-29a along with elevated miR-122 serve as a diagnostic panel for NAFLD [29]
SerumDownnegatively correlated with necroinflammation and liver fibrosis [30]
Serum DownBiomarker of advanced liver cirrhosis [32]
Serum UpBiomarker of HCC [67]
PlasmaDownPrognostic marker of poor outcome of HCC [33]
SerumUpPredictor for poor survival of HCC [70]
HCC tissueUpPredictor for recurrence of HCC [35]
HCC tissueDownPrognostic marker of poor outcome of HCC [55]
HCC tissueDown Predictor for low survival rate of HCC [36]

Share and Cite

MDPI and ACS Style

Lin, H.-Y.; Yang, Y.-L.; Wang, P.-W.; Wang, F.-S.; Huang, Y.-H. The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond. Cells 2020, 9, 1041. https://doi.org/10.3390/cells9041041

AMA Style

Lin H-Y, Yang Y-L, Wang P-W, Wang F-S, Huang Y-H. The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond. Cells. 2020; 9(4):1041. https://doi.org/10.3390/cells9041041

Chicago/Turabian Style

Lin, Hung-Yu, Ya-Ling Yang, Pei-Wen Wang, Feng-Sheng Wang, and Ying-Hsien Huang. 2020. "The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond" Cells 9, no. 4: 1041. https://doi.org/10.3390/cells9041041

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop