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MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH

Developmental Epigenetics Group, Liggins Institute, The University of Auckland, 85 Park Road, Grafton, Auckland 1023, New Zealand
Author to whom correspondence should be addressed.
J. Clin. Med. 2015, 4(11), 1938-1950;
Submission received: 20 August 2015 / Revised: 9 November 2015 / Accepted: 10 November 2015 / Published: 16 November 2015
(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)


Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern “epidemic” of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver’s limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of “extra-hepatic fat”, a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body’s attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis.
diet; miRNA; NAFLD; NASH

1. Diet-Induced Fatty Liver Disease

A combination of dietary-based caloric excess and a sedentary lifestyle (confounded by socioeconomic factors) has led to population-wide weight gain and, subsequently, an increasing incidence of obesity-related comorbidities (e.g., non-alcoholic fatty liver (NAFLD), type 2 diabetes mellitus (T2DM) and cardiovascular diseases) [1,2]. In addition to driving the uptake and “storage” of excess circulating fatty acids (FAs) into peripheral tissues, this generalized metabolic syndrome (MetS) is also characterized by elevated triglyceride (TG) synthesis, leading to yet further fat accumulation, particularly in liver and adipose tissues [3] (Figure 1). The abnormal accumulation of fat in the liver (occurring in the absence of significant alcohol consumption) is a defining characteristic of NAFLD and begins with the intra-cytoplasmic accumulation of TG as liposomes around the hepatocyte nucleus. At more advanced stages, these vesicles increase in size, such that the nucleus is distorted and displaced to the periphery of the hepatocyte, a condition that is known as macrovesicular steatosis [4]. The pathological spectrum of NAFLD progresses then to non-alcoholic steatohepatitis (NASH), which is defined by the additional degeneration of the hepatocytes and sinusoidal fibrosis [4,5] and, finally, to end-stage cirrhosis, the main driver of liver transplant interventions [6,7].
Lipids are not only important as structural components of cell membranes (in the form of cholesterol and phospholipids) and energy storage (in the form of TG), but also serve as signalling molecules. Although generally sourced through the diet, fatty acids are also synthesized de novo as a normal function of hepatocyte cells [8]. However, abnormally elevated hepatic FA biosynthesis can precipitate glucose intolerance and insulin resistance (IR) as a consequence of the systemic attempt to restore homeostasis by promoting fat turnover [9]. By driving lipolysis, this adaptive mechanism unfortunately results in further increases in the circulating level of TG-derived free fatty acids (FFAs) [10]. Furthermore, the pathogenesis of IR is commonly accompanied by inflammation [11,12], which in turn stimulates the secretion of hepatokines [11,13,14,15]. Consequently, the progression of liver disease often occurs in parallel with that of MetS.

2. MicroRNAs in Metabolic Syndrome and NAFLD

MicroRNAs (miRNAs) are a class of endogenous, short, non-protein coding, single-stranded gene products, typically 20–22 nucleotides long [16]. The majority of miRNAs are intracellular [17] and encoded in the introns of protein-coding genes [18]. The primary miRNA is transcribed in the nucleus and subsequently integrated into the RNA-induced silencing complex in cytoplasm [19] to regulate the expression of target genes [20,21]. They are present in genomes across all eukaryotic organisms and are thought to modulate the expression of target genes post-transcriptionally via interactions with specific mRNAs [22].
Figure 1. Hepatic triglyceride (TG) accumulation. FFAs are derived from the diet or synthesized de novo by hepatocytes. High levels of dietary protein intake (leading to increased circulating BCAA) can induce peripheral IR by inhibiting insulin signaling, resulting in increased uptake of glucose and TG storage in hepatocytes. Meanwhile, IR in adipose tissue reduces the inhibitory effect of insulin on lipoprotein lipase, resulting in increased lipolysis (i.e., breakdown of TG) and, thus, to increased circulating FAs to be taken up by the liver. Hyperinsulinemia can also induce de novo synthesis of FFAs in hepatocytes, leading to hepatic TG synthesis. These pathways drive hepatic TG accumulation and ultimately may contribute to the development of NASH. IR: insulin resistance; FFA: free fatty acid; BCAA: branched-chain amino acid; NASH: non-alcoholic steatohepatitis; VLDL: very low-density lipoprotein.
Figure 1. Hepatic triglyceride (TG) accumulation. FFAs are derived from the diet or synthesized de novo by hepatocytes. High levels of dietary protein intake (leading to increased circulating BCAA) can induce peripheral IR by inhibiting insulin signaling, resulting in increased uptake of glucose and TG storage in hepatocytes. Meanwhile, IR in adipose tissue reduces the inhibitory effect of insulin on lipoprotein lipase, resulting in increased lipolysis (i.e., breakdown of TG) and, thus, to increased circulating FAs to be taken up by the liver. Hyperinsulinemia can also induce de novo synthesis of FFAs in hepatocytes, leading to hepatic TG synthesis. These pathways drive hepatic TG accumulation and ultimately may contribute to the development of NASH. IR: insulin resistance; FFA: free fatty acid; BCAA: branched-chain amino acid; NASH: non-alcoholic steatohepatitis; VLDL: very low-density lipoprotein.
Jcm 04 01938 g001
MicroRNA activity is known to impact a diverse range of biological processes, including cellular growth and development, cardiovascular and cerebrovascular function, protein secretion and glucose and fatty acid metabolism [8,16,23,24,25]. Their potential importance for regulating metabolic homeostasis is also becoming clear. For example, the antisense targeting of just miR-122 in high-fat fed mice leads to a significant 30% decrease in circulating cholesterol levels [26,27], hepatic cholesterol and fatty acids biosynthesis and elevated fatty acid β-oxidation associated with a reduction in TG and hepatosteatosis [26]. Further, miR-33a and miR-33b are co-transcribed with their respective human host genes SREBP2 and SREBP1 [28], the sterol regulatory element-binding protein (SREBP) family of transcription factors being key regulators of many genes involved in FA and cholesterol biosynthesis, as well as TG and phospholipids production. miR-33a and miR-33b both target and act on the α-subunit of AMP-activated protein kinase (AMPK) [8,29,30]. In response to low cellular energy levels, AMPK decreases energy-consuming processes (such as FA biogenesis) to promote ATP synthesis. AMPK inhibits the activity of SREBPs and, by catalysing phosphorylation, activates their target substrates, such as acetyl-CoA carboxylase (ACC)-1. Therefore, inhibition of AMPK expression via miR-33 leads to the stimulation of SREBPs (and their target genes) to increase intracellular levels of TG, cholesterol and FAs.
A number of miRNAs have been reported to be dysregulated in rodent models of NAFLD, obesity and T2DM, in some cases aligning with the changes observed in obese human patients with NAFLD and NASH [31,32,33]. Notably, miR-200a/b and miR-429, key members of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429), are all upregulated with disease. In addition, miR-451, miR-27a and miR-122 are downregulated in the liver of rats fed with a diet of high fat or high fructose or their combination [34]. Also reported as suppressed are miR-29c in diet-induced NASH [35] and miR-21, miR-29c and miR-451 in livers of ob/ob mice with fatty liver [36]. miR-34a is yet another species that is particularly associated with hepatic metabolic diseases, being highly expressed in patients with steatosis and NASH [32], as well as T2DM subjects [33]. In particular, miR-34a expression increases with the severity of NASH [37]. Castro et al. have demonstrated that miR-34a expression, upon stimulation by ursodeoxycholic acid (UDCA) (a potent inhibitor of apoptosis), inhibits p53 via the miR34a/sirtuin (SIRT)-1/p53 pathway in primary hepatocytes. In turn, p53 modulates miR-34a expression through a positive feedback loop and highlights the important role of miR-34a in regulating hepatocyte apoptosis and NAFLD progression [37]. The link with SIRT-1 is also clear evidence that miRNAs influence metabolism. SIRT-1 has recently been identified as a critical central metabolic regulator that is responsive to intracellular NAD+ levels and, by de-acetylating both histone and non-histone targets, alters the expression of genes involved in lipid and cholesterol synthesis and energy homeostasis, including proliferator-activated receptors (PPARs), proliferator-activated receptor gamma coactivator 1-α (PGC-1α), forkhead box-protein 1 (FOXO1), p53 and SREBPs [38,39,40].
MiR-335 is also highly expressed in obese mice [41] and is encoded within an intronic region of the imprinted gene MEST [42], although the transcriptional control of miR-335 is independent of the host gene [41]. While MEST has been reported to enhance the capacity for lipid storage in adipocytes [43], miR-335 is upregulated in the liver and adipose tissue of diabetic db/db mice and promotes lipid accumulation during adipocyte differentiation in the murine 3T3-L1 cell model [41]. It has also been linked with adipose tissue inflammation [44] and more recently shown to inhibit hepatic stellate cell activation and migration, suggesting a potentially positive role in reducing hepatic fibrosis [45]. Given that liver fibrosis and increased TG (both in liver and in circulation) are characteristics of NAFLD, miR-335 presents a potentially valuable therapeutic candidate for the diagnosis and treatment of NAFLD. In our own studies, we have found that circulating miR-335 is significantly decreased after weight loss in obese patients with T2DM who underwent gastric bypass (GBP) bariatric surgery and that this reduction in miR-335 level was strongly correlated with BMI [46]. It has previously been reported that circulating levels of the hepatokine fetuin A (FetA), a glycoprotein shown to promote lipid-induced insulin resistance [47], decrease after GBP surgery in obese subjects with T2DM [48]. Using the approach of RNA interference-mediated knockdown in the liver cell line HepG2, we have demonstrated that miR-335 mediates the increase in FetA expression that results from incubation with the FFA palmitate.
In these same studies, we also showed that the palmitate-induced increase in FetA expression is myostatin (MSTN)-dependent [46]. A member of the transforming growth factor-β (TGF-β) superfamily, MSTN is classically known as a regulator of skeletal muscle growth. However, elevated MSTN expression (circulating and intracellular) is associated with metabolic disorders, such as obesity [49] and type 1 diabetes mellitus (T1DM) [50]. The secreted form of MSTN is strongly correlated with human obesity [49] and weight loss [51], suggesting an emergent and important role for MSTN in the regulation of energy metabolism. Further, murine models of loss-of-function MSTN mutations [52], gene knockout [53] or pro-peptide overexpression [54] are all resistant to high fat diet-induced IR and obesity. Indeed, MSTN depletion attenuates adipose formation and reduces hepatic steatosis in high fat diet-induced obese mice [53]. In the context of NAFLD, the importance of miRNA in regulating MSTN function remains to be fully elucidated. However, we have shown that miRNA-dependent MSTN activity mediates both hepatic TG levels and biosynthesis in response to leucine, a branched-chain amino acid (BCAA), which is known to be elevated in obese and IR patients [55] and in subjects progressing from steatosis to NASH [56]. Notably, miR-143 and miR-92b modulated the MSTN-dependent regulation of key metabolic genes involved in glucose uptake and TG accumulation in HepG2 cells supplemented with leucine [55]. Given that elevated TG and insulin resistance are common features of NAFLD, miR-143 and miR-92b present potential candidate interventions in NAFLD, although how these miRNAs may be involved in the regulation of lipid homeostasis remains to be fully investigated.

3. The Clinical Relevance of Exosomal Signalling in NAFLD

While an initial diagnosis of NAFLD can be made with modern imaging technologies, a definitive diagnosis of NASH requires confirmation by liver biopsy [57]. However, the invasive nature of this procedure often deters patient uptake, suggesting that the prevalence of NAFLD worldwide is likely to be understated. Furthermore, the inherent sampling variability associated with the biopsy process makes accurate histopathological diagnosis difficult and unreliable [57]. Meanwhile, the metabolites currently used to assess metabolic disease (such as ALT and AST) by computed tomography (CT) are not sufficiently correlated to liver disease to be specifically useful for accurate monitoring of progression, nor to account for differences between patients in various stages of NAFLD [58].
Early indications suggest that miRNA profiles measured in readily-sourced plasma and serum samples may however represent a new diagnostic approach for liver diseases [59]. Several differentially-expressed miRNA species have specifically been reported in plasma samples of NAFLD subjects. In particular, miR-16 is significantly overexpressed in both human and rats with steatosis/NASH compared to healthy subjects [32], while in patients with NAFLD, miR-21, miR-122, miR-192, miR-375, miR-19a, miR-19b and miR-146b are all significantly upregulated [32,59,60,61,62,63]. Furthermore, the level of expression for particular miRNAs appears to correlate with the severity of clinical histopathology, notably miR-181a, miR-34a, miR-122, miR-200 and miR-192, while miR-34a exhibits the strongest correlation with a histopathology score in mice with fat-induced liver injury [62]. Interestingly, increased miR-192, miR-375 and miR-122 distinguish more advanced NASH compared to simple steatosis, while miR-122 distinguishes liver fibrosis specifically [59].
In this review, we have described a number of miRNAs (summarized in Table 1) that are clearly associated with steatosis/NASH and have sought to highlight those that may underpin diagnostic profiles in “soluble biopsy” samples. Since miRNAs generally show a great degree of stability in extracellular environments (including blood) that contain active ribonucleases, it is clear that secreted miRNAs must be packaged to protect against degradation [17]. Generally, this involves incorporation into either exosomes [64] or RNA-binding protein complexes [65], and this enables their efficient recovery from biofluid clinical samples [66]. Notably, upregulation of both miR-122 and miR-155 following inflammation, and the related pathology alcoholic liver disease (ASH), has been reported in exosome-rich biochemical fractions from serum [67]. As components of exosomes, secreted miRNAs are intended to mediate inter-tissue communication, often following pathological challenges [68,69], and specifically to coordinate systemic responses between the primary tissue, which exports them and the cells at secondary sites [17]. Critically, there is already evidence for some species (notably miR-122, miR-34a and miR-200a) being similarly elevated with disease in both intra-hepatocyte tissue samples and serum/blood samples. This inter-tissue concordance encourages the view that liver-specific miRNA profiles of disease can be accurately assessed by interrogation of exosome fractions derived from more easily-obtained soluble biopsies.
We are unaware of any miRNA-based therapeutic candidate for NAFLD currently being tested by a clinical trial. Although many miRNAs represent attractive potential therapeutic targets for intervening in disease progression, the efficient delivery of an effector molecule remains a significant challenge for RNA interference-based approaches to treatment. As delivery of miRNA mimics or antagomirs may lead to rapid degradation of the naked molecules, it is likely that they will need to be incorporated into stable vehicles, such as nucleic acid lipid particles or lipid bilayers coated with polyethylene glycol or conjugated to cholesterol, in order to be taken up by liver [70,71]. However, the injection of miR-122 antagomir in the form of a “locked nucleic acid” (LNA)-modified oligonucleotide has been shown to suppress viremia in chronically hepatitis C viral-infected chimpanzees [72]. Indeed, an miR-122-based therapeutic approach has successfully undergone phase IIa human clinical trials for the treatment of hepatic viral infection [73], encouraging the view that the extension of miRNA-based approaches to NAFLD-related syndrome may be on the near horizon.
Table 1. List of miRNAs involved in different biological processes of hepatic lipid homeostasis.
Table 1. List of miRNAs involved in different biological processes of hepatic lipid homeostasis.
Biological SamplesmiRNA(s)OutcomeTarget *References
PlasmamiR-122Inhibition of miR-122 reduced hepatic cholesterol and FA biosynthesis and elevated FA oxidation in humansSREBP-1c, SREBP-2[26,27,32]
IntracellularmiR-122, miR-451, miR-27aDownregulated in the liver of high fat/fructose-fed rats miR-451→NFκB[34,74,75]
Plasma/IntracellularmiR-33a/b, miR-143, miR-92bInhibition of miR-33a/b increased HDL and lowers VLDLSREBP-1, SREBP-2, AMPKα, IRS2, MSTN, FOXO1[29,30,55]
Overexpression of miR-33a/b increased HDL and reduces VLDL
Plasma/IntracellularmiR-34a, miR-16, miR-21, miR-27b, miR-122, miR-192, miR-375, miR-19a/b, miR-146b, miR-181a, miR-200Overexpressed in circulation of steatotic, NASH and T2DM humans/ratsmiR-34a→p53[32,33,61,62,76,77,78,79]
miR-27b→ PPARγ
miR-146b→IL-6, TNF-α
IntracellularmiR-200a/b, miR-429 Upregulated in the liver of high-fat/fructose-fed rats [34]
IntracellularmiR-29cDownregulated in the liver of ob/ob mice on a lipogenic diet [35]
PlasmamiR-192, miR-375, miR-122Increased particularly in NASH, suppression of glucose-induced insulin secretionmiR-375→HMG-CoA[32,62,80]
PlasmamiR-155, miR-122Upregulated in rats with ASHmiR-155→LXRα[67,81]
ASH: alcoholic steatohepatitis; FA(s): fatty acid(s); HMG-CoA: 3-hydroxy-3-methyl-glutaryl-CoA; NAFLD: non-alcoholic fatty liver; NASH: non-alcoholic steatohepatitis; SREBP: sterol regulatory element-binding protein; p53: Tumour protein p53; T2DM: type 2 diabetes mellitus; TG: triglyceride. * Genes are listed as human homologs.

4. Conclusions

While the precise molecular mechanisms underlying progression to NAFLD remain unclear, the emerging importance of miRNAs in the context of this disease suggests that they may represent valuable diagnostic tools. Although no miRNA-based trials are yet underway to address their utility as potential intervention strategies, a growing body of literature suggests that miRNA profiles reflective of disease progression and measured in readily-obtainable (least invasive) “liquid biopsies” offer considerable promise for assessing both risk and disease status along the NAFLD spectrum of pathologies. Critically, such tools would help to overcome current clinical limitations to the identification and accurate diagnostic assessment of “at risk” individuals, the numbers of which appear to be increasing as the epidemic of metabolic syndrome continues.


Aida Zarfeshani is supported by a University of Auckland Doctoral Scholarship and the Liggins institute Doctoral Scholarship Fund. The funders played no role in the conception or design of this study, the data collection and analysis, the decision to publish nor the preparation of this manuscript. There are no potential conflicts of interest relevant to this article.

Author Contributions

Aida Zarfeshani wrote the preliminary draft of the manuscript, reviewed the manuscript and edited the manuscript. Sherry Ngo and Allan M. Sheppard reviewed and edited the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Kopelman, P.G. Obesity as a medical problem. Nature 2000, 404, 635–643. [Google Scholar] [PubMed]
  2. Mokdad, A.H.; Ford, E.S.; Bowman, B.A.; Dietz, W.H.; Vinicor, F.; Bales, V.S.; Marks, J.S. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003, 289, 76–79. [Google Scholar] [CrossRef] [PubMed]
  3. Spiegelman, B.M.; Flier, J.S. Obesity and the regulation of energy balance. Cell 2001, 104, 531–543. [Google Scholar] [CrossRef]
  4. Goldman, L.; Ausiello, D. Cecil Textbook of Medicine; Arjomand, M.; Setudenia, A.H.; Qasemi, Sh., Translators; Nasle Farda: Tehran, Iran, 2003; Volume 11. [Google Scholar]
  5. Lara-Castro, C.; Garvey, W.T. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol. Metab. Clin. N. Am. 2008, 37, 841–856. [Google Scholar] [CrossRef] [PubMed]
  6. Bullock, R.E.; Zaitoun, A.M.; Aithal, G.P.; Ryder, S.D.; Beckingham, I.J.; Lobo, D.N. Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma. J. Hepatol. 2004, 41, 685–686. [Google Scholar] [CrossRef] [PubMed]
  7. Marrero, J.A.; Fontana, R.J.; Su, G.L.; Conjeevaram, H.S.; Emick, D.M.; Lok, A.S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002, 36, 1349–1354. [Google Scholar] [CrossRef] [PubMed]
  8. Rottiers, V.; Näär, A.M. MicroRNAs in metabolism and metabolic disorders. Nat. Rev. Mol. Cell Biol. 2012, 13, 239–250. [Google Scholar] [CrossRef] [PubMed]
  9. Yahagi, N.; Shimano, H.; Matsuzaka, T.; Sekiya, M.; Najima, Y.; Okazaki, S.; Okazaki, H.; Tamura, Y.; Iizuka, Y.; Inoue, N. p53 involvement in the pathogenesis of fatty liver disease. J. Biol. Chem. 2004, 279, 20571–20575. [Google Scholar] [CrossRef] [PubMed]
  10. Sethi, J.K.; Vidal-Puig, A.J. Thematic review series: Adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J. Lipid Res. 2007, 48, 1253–1262. [Google Scholar] [CrossRef] [PubMed]
  11. Stefan, N.; Kantartzis, K.; Machann, J.; Schick, F.; Thamer, C.; Rittig, K.; Balletshofer, B.; Machicao, F.; Fritsche, A.; Häring, H.-U. Identification and characterization of metabolically benign obesity in humans. Arch. Intern. Med. 2008, 168, 1609–1616. [Google Scholar] [CrossRef] [PubMed]
  12. Fabbrini, E.; Magkos, F.; Mohammed, B.S.; Pietka, T.; Abumrad, N.A.; Patterson, B.W.; Okunade, A.; Klein, S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl. Acad. Sci. USA 2009, 106, 15430–15435. [Google Scholar] [CrossRef] [PubMed]
  13. Misu, H.; Takamura, T.; Takayama, H.; Hayashi, H.; Matsuzawa-Nagata, N.; Kurita, S.; Ishikura, K.; Ando, H.; Takeshita, Y.; Ota, T. A liver-derived secretory protein, selenoprotein P causes insulin resistance. Cell Metab. 2010, 12, 483–495. [Google Scholar] [CrossRef] [PubMed]
  14. Yang, S.; Hwang, S.; Choi, H.; Yoo, H.; Seo, J.; Kim, S.; Kim, N.; Baik, S.; Choi, D.; Choi, K.; Choi, K. Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: Implications for insulin resistance, inflammation, and atherosclerosis. J. Clin. Endocrinol. Metab. 2011, 96, E1325–E1329. [Google Scholar] [CrossRef] [PubMed]
  15. Misu, H.; Ishikura, K.; Kurita, S.; Takeshita, Y.; Ota, T.; Saito, Y.; Takahashi, K.; Kaneko, S.; Takamura, T. Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes. PLoS ONE 2012, 7, e34952. [Google Scholar] [CrossRef] [PubMed]
  16. Williams, M.D.; Mitchell, G.M. MicroRNAs in insulin resistance and obesity. Exp. Diabetes Res. 2012, 2012. [Google Scholar] [CrossRef] [PubMed]
  17. Etheridge, A.; Lee, I.; Hood, L.; Galas, D.; Wang, K. Extracellular microRNA: A new source of biomarkers. Mutat. Res. Fundam. Mol. Mech. Mutagen. 2011, 717, 85–90. [Google Scholar] [CrossRef] [PubMed]
  18. Aravin, A.A.; Lagos-Quintana, M.; Yalcin, A.; Zavolan, M.; Marks, D.; Snyder, B.; Gaasterland, T.; Meyer, J.; Tuschl, T. The small RNA profile during Drosophila melanogaster development. Dev. Cell 2003, 5, 337–350. [Google Scholar] [CrossRef]
  19. Ketting, R.F. MicroRNA biogenesis and function. In Regulation of microRNAs; Springer: Basel, Switzerland, 2010; pp. 1–14. [Google Scholar]
  20. Lim, L.P.; Lau, N.C.; Garrett-Engele, P.; Grimson, A.; Schelter, J.M.; Castle, J.; Bartel, D.P.; Linsley, P.S.; Johnson, J.M. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005, 433, 769–773. [Google Scholar] [CrossRef] [PubMed]
  21. Pillai, R.S.; Bhattacharyya, S.N.; Artus, C.G.; Zoller, T.; Cougot, N.; Basyuk, E.; Bertrand, E.; Filipowicz, W. Inhibition of translational initiation by Let-7 microRNA in human cells. Science 2005, 309, 1573–1576. [Google Scholar] [CrossRef] [PubMed]
  22. Valinezhad Orang, A.; Safaralizadeh, R.; Kazemzadeh-Bavili, M. Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. Int. J. Genomics 2014, 2014. [Google Scholar] [CrossRef] [PubMed]
  23. Gauthier, B.R.; Wollheim, C.B. MicroRNAs: “ribo-regulators” of glucose homeostasis. Nat. Med. 2006, 12, 36–38. [Google Scholar] [CrossRef] [PubMed]
  24. He, A.; Zhu, L.; Gupta, N.; Chang, Y.; Fang, F. Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Mol. Endocrinol. 2007, 21, 2785–2794. [Google Scholar] [CrossRef] [PubMed]
  25. Poy, M.; Spranger, M.; Stoffel, M. microRNAs and the regulation of glucose and lipid metabolism. Diabetes Obes. Metab. 2007, 9, 67–73. [Google Scholar] [CrossRef] [PubMed]
  26. Esau, C.; Davis, S.; Murray, S.F.; Yu, X.X.; Pandey, S.K.; Pear, M.; Watts, L.; Booten, S.L.; Graham, M.; McKay, R. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006, 3, 87–98. [Google Scholar] [CrossRef] [PubMed]
  27. Krützfeldt, 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] [PubMed]
  28. Rottiers, V.; Najafi-Shoushtari, S.H.; Kristo, F.; Gurumurthy, S.; Zhong, L.; Li, Y.; et al. MicroRNAs in metabolism and metabolic diseases. Cold Spring Harb. Symp. Quant. Biol. 2011, 76, 225–233. [Google Scholar] [CrossRef] [PubMed]
  29. Dávalos, A.; Goedeke, L.; Smibert, P.; Ramírez, C.M.; Warrier, N.P.; Andreo, U.; Cirera-Salinas, D.; Rayner, K.; Suresh, U.; Pastor-Pareja, J.C. 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] [PubMed]
  30. Rayner, K.J.; Esau, C.C.; Hussain, F.N.; McDaniel, A.L.; Marshall, S.M.; van Gils, J.M.; Ray, T.D.; Sheedy, F.J.; Goedeke, L.; Liu, X. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 2011, 478, 404–407. [Google Scholar] [CrossRef] [PubMed]
  31. Trajkovski, M.; Hausser, J.; Soutschek, J.; Bhat, B.; Akin, A.; Zavolan, M.; Heim, M.H.; Stoffel, M. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 2011, 474, 649–653. [Google Scholar] [CrossRef] [PubMed]
  32. Cheung, O.; Puri, P.; Eicken, C.; Contos, M.J.; Mirshahi, F.; Maher, J.W.; Kellum, J.M.; Min, H.; Luketic, V.A.; Sanyal, A.J. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology 2008, 48, 1810–1820. [Google Scholar] [CrossRef] [PubMed]
  33. Kong, L.; Zhu, J.; Han, W.; Jiang, X.; Xu, M.; Zhao, Y.; Dong, Q.; Pang, Z.; Guan, Q.; Gao, L. Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: A clinical study. Acta Diabetol. 2011, 48, 61–69. [Google Scholar] [CrossRef] [PubMed]
  34. Alisi, A.; da Sacco, L.; Bruscalupi, G.; Piemonte, F.; Panera, N.; De Vito, R.; Leoni, S.; Bottazzo, G.F.; Masotti, A.; Nobili, V. Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. Lab. Investig. 2011, 91, 283–293. [Google Scholar] [CrossRef] [PubMed]
  35. Pogribny, I.P.; Starlard-Davenport, A.; Tryndyak, V.P.; Han, T.; Ross, S.A.; Rusyn, I.; Beland, F.A. Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab. Investig. 2010, 90, 1437–1446. [Google Scholar] [CrossRef] [PubMed]
  36. Li, S.; Chen, X.; Zhang, H.; Liang, X.; Xiang, Y.; Yu, C.; Zen, K.; Li, Y.; Zhang, C.-Y. Differential expression of microRNAs in mouse liver under aberrant energy metabolic status. J. Lipid Res. 2009, 50, 1756–1765. [Google Scholar] [CrossRef] [PubMed]
  37. Castro, R.E.; Ferreira, D.M.; Afonso, M.B.; Borralho, P.M.; Machado, M.V.; Cortez-Pinto, H.; Rodrigues, C.M. miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease. J. Hepatol. 2013, 58, 119–125. [Google Scholar] [CrossRef] [PubMed]
  38. Kemper, J.K.; Xiao, Z.; Ponugoti, B.; Miao, J.; Fang, S.; Kanamaluru, D.; Tsang, S.; Wu, S.-Y.; Chiang, C.-M.; Veenstra, T.D. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 2009, 10, 392–404. [Google Scholar] [CrossRef] [PubMed]
  39. Motta, M.C.; Divecha, N.; Lemieux, M.; Kamel, C.; Chen, D.; Gu, W.; Bultsma, Y.; McBurney, M.; Guarente, L. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004, 116, 551–563. [Google Scholar] [CrossRef]
  40. Ponugoti, B.; Kim, D.-H.; Xiao, Z.; Smith, Z.; Miao, J.; Zang, M.; Wu, S.-Y.; Chiang, C.-M.; Veenstra, T.D.; Kemper, J.K. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J. Biol. Chem. 2010, 285, 33959–33970. [Google Scholar] [CrossRef] [PubMed]
  41. Nakanishi, N.; Nakagawa, Y.; Tokushige, N.; Aoki, N.; Matsuzaka, T.; Ishii, K.; Yahagi, N.; Kobayashi, K.; Yatoh, S.; Takahashi, A. The up-regulation of microRNA-335 is associated with lipid metabolism in liver and white adipose tissue of genetically obese mice. Biochem. Biophys. Res. Commun. 2009, 385, 492–496. [Google Scholar] [CrossRef] [PubMed]
  42. Dohi, O.; Yasui, K.; Gen, Y.; Takada, H.; Endo, M.; Tsuji, K.; Konishi, C.; Yamada, N.; Mitsuyoshi, H.; Yagi, N. Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma. Int. J. Oncol. 2013, 42, 411–418. [Google Scholar] [PubMed]
  43. Takahashi, M.; Kamei, Y.; Ezaki, O. Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size. Am. J. Physiol. Endocrinol. Metab. 2005, 288, E117–E124. [Google Scholar] [CrossRef] [PubMed]
  44. Zhu, L.; Chen, L.; Shi, C.-M.; Xu, G.-F.; Xu, L.-L.; Zhu, L.-L.; Ni, Y.; Cui, Y.; Ji, C. MiR-335, an adipogenesis-related microRNA, is involved in adipose tissue inflammation. Cell Biochem. Biophys. 2014, 68, 283–290. [Google Scholar] [CrossRef] [PubMed]
  45. Chen, C.; Wu, C.-Q.; Zhang, Z.-Q.; Yao, D.-K.; Zhu, L. Loss of expression of miR-335 is implicated in hepatic stellate cell migration and activation. Exp. Cell Res. 2011, 317, 1714–1725. [Google Scholar] [CrossRef] [PubMed]
  46. Zarfeshani, A.; Ngo, S.; Murphy, R.; Sheppard, A.M. MiRNAs as bariatric surgery outcome biomarkers and hepatokine regulators after GBP but not SG. Mol. End. 2015. Submitted. [Google Scholar]
  47. Pal, D.; Dasgupta, S.; Kundu, R.; Maitra, S.; Das, G.; Mukhopadhyay, S.; Ray, S.; Majumdar, S.S.; Bhattacharya, S. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 2012, 18, 1279–1285. [Google Scholar] [CrossRef] [PubMed]
  48. Jüllig, M.; Yip, S.; Xu, A.; Smith, G.; Middleditch, M.; Booth, M.; Babor, R.; Beban, G.; Murphy, R. Lower fetuin-A retinol binding protein 4 and several metabolites after gastric bypass compared to sleeve gastrectomy in patients with type 2 diabetes. PLoS ONE 2014, 9, e96489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Hittel, D.S.; Berggren, J.R.; Shearer, J.; Boyle, K.; Houmard, J.A. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 2009, 58, 30–38. [Google Scholar] [CrossRef] [PubMed]
  50. Chen, Y.; Cao, L.; Ye, J.; Zhu, D. Upregulation of myostatin gene expression in streptozotocin-induced type 1 diabetes mice is attenuated by insulin. Biochem. Biophys. Res. Commun. 2009, 388, 112–116. [Google Scholar] [CrossRef] [PubMed]
  51. Milan, G.; Dalla Nora, E.; Pilon, C.; Pagano, C.; Granzotto, M.; Manco, M.; Mingrone, G.; Vettor, R. Changes in muscle myostatin expression in obese subjects after weight loss. J. Clin. Endocrinol. Metab. 2004, 89, 2724–2727. [Google Scholar] [CrossRef] [PubMed]
  52. Schuelke, M.; Wagner, K.R.; Stolz, L.E.; Hübner, C.; Riebel, T.; Kömen, W.; Braun, T.; Tobin, J.F.; Lee, S.-J. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 2004, 350, 2682–2688. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, C.; McFarlane, C.; Lokireddy, S.; Masuda, S.; Ge, X.; Gluckman, P.D.; Sharma, M.; Kambadur, R. Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice. Diabetologia 2012, 55, 183–193. [Google Scholar] [CrossRef] [PubMed]
  54. Zhao, B.; Wall, R.J.; Yang, J. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem. Biophys. Res. Commun. 2005, 337, 248–255. [Google Scholar] [CrossRef] [PubMed]
  55. Zarfeshani, A.; Ngo, S.; Sheppard, A.M. Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway-potential implications for nonalcoholic fatty liver disease. Clin. Epigenet. 2014, 6, 27. [Google Scholar] [CrossRef] [PubMed]
  56. Lake, A.D.; Novak, P.; Shipkova, P.; Aranibar, N.; Robertson, D.G.; Reily, M.D.; Lehman-McKeeman, L.D.; Vaillancourt, R.R.; Cherrington, N.J. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015, 47, 603–615. [Google Scholar] [CrossRef] [PubMed]
  57. Castera, L.; Vilgrain, V.; Angulo, P. Noninvasive evaluation of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 666–675. [Google Scholar] [CrossRef] [PubMed]
  58. Lee, S.-K. Exosomes and Microvesicles as Biomarkers in Metabolic Diseases. Korean J. Obes. 2014, 23, 150–155. [Google Scholar] [CrossRef]
  59. Pirola, C.J.; Gianotti, T.F.; Castaño, G.O.; Mallardi, P.; San Martino, J.; Ledesma, M.M.G.L.; 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 2014. [Google Scholar] [CrossRef] [PubMed]
  60. McArdle, M.A.; Finucane, O.M.; Connaughton, R.M.; McMorrow, A.M.; Roche, H.M. Mechanisms of obesity-induced inflammation and insulin resistance: Insights into the emerging role of nutritional strategies. Front. Endocrinol. 2013, 4. [Google Scholar] [CrossRef] [PubMed]
  61. Gori, M.; Arciello, M.; Balsano, C. MicroRNAs in nonalcoholic fatty liver disease: Novel biomarkers and prognostic tools during the transition from steatosis to hepatocarcinoma. BioMed. Res. Int. 2014, 2014. [Google Scholar] [CrossRef] [PubMed]
  62. 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. Pharmacol. 2012, 262, 52–59. [Google Scholar] [CrossRef] [PubMed]
  63. Celikbilek, M.; Baskol, M.; Taheri, S.; Deniz, K.; Dogan, S.; Zararsiz, G.; Gursoy, S.; Guven, K.; Ozbakır, O.; Dundar, M.; Yucesoy, M. Circulating microRNAs in patients with non-alcoholic fatty liver disease. World J. Hepatol. 2014, 6, 613. [Google Scholar] [PubMed]
  64. Gallo, A.; Tandon, M.; Alevizos, I.; Illei, G.G. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE 2012, 7, e30679. [Google Scholar] [CrossRef] [PubMed]
  65. Arroyo, J.D.; Chevillet, J.R.; Kroh, E.M.; Ruf, I.K.; Pritchard, C.C.; Gibson, D.F.; Mitchell, P.S.; Bennett, C.F.; Pogosova-Agadjanyan, E.L.; Stirewalt, D.L.; et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl. Acad. Sci. USA 2011, 108, 5003–5008. [Google Scholar] [CrossRef] [PubMed]
  66. Berger, F.; Reiser, M.F. Micro-RNAs as potential new molecular biomarkers in oncology: Have they reached relevance for the clinical imaging sciences? Theranostics 2013, 3, 943. [Google Scholar] [CrossRef] [PubMed]
  67. Chen, Y.-P.; Jin, X.; Xiang, Z.; Chen, S.-H.; Li, Y.-M. Circulating MicroRNAs as potential biomarkers for alcoholic steatohepatitis. Liver Int. 2013, 33, 1257–1265. [Google Scholar] [CrossRef] [PubMed]
  68. Boeri, M.; Verri, C.; Conte, D.; Roz, L.; Modena, P.; Facchinetti, F.; Calabrò, E.; Croce, C.M.; Pastorino, U.; Sozzi, G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc. Natl. Acad. Sci. USA 2011, 108, 3713–3718. [Google Scholar] [CrossRef] [PubMed]
  69. Lu, Z.; Liu, M.; Stribinskis, V.; Klinge, C.; Ramos, K.; Colburn, N.; Li, Y. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 2008, 27, 4373–4379. [Google Scholar] [CrossRef] [PubMed]
  70. Morrissey, D.V.; Lockridge, J.A.; Shaw, L.; Blanchard, K.; Jensen, K.; Breen, W.; Hartsough, K.; Polisky, B. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol. 2005, 23, 1002–1007. [Google Scholar] [CrossRef] [PubMed]
  71. Wolfrum, C.; Shi, S.; Jayaprakash, K.N.; Jayaraman, M.; Wang, G.; Pandey, R.K.; Rajeev, K.G.; Nakayama, T.; Charrise, K.; Ndungo, E.M. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat. Biotechnol. 2007, 25, 1149–1157. [Google Scholar] [CrossRef] [PubMed]
  72. Lanford, R.E.; Hildebrandt-Eriksen, E.S.; Petri, A.; Persson, R.; Lindow, M.; Munk, M.E.; Kauppinen, S.; Ørum, H. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010, 327, 198–201. [Google Scholar] [CrossRef] [PubMed]
  73. Janssen, H.L.; Reesink, H.W.; Lawitz, E.J.; Zeuzem, S.; Rodriguez-Torres, M.; Patel, K.; van der Meer, A.J.; Patick, A.K.; Chen, A.; Zhou, Y. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 2013, 368, 1685–1694. [Google Scholar] [CrossRef] [PubMed]
  74. Hur, W.; Lee, J.H.; Kim, S.W.; Kim, J.-H.; Bae, S.H.; Kim, M.; Park, T.; Um, S.-J. Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway. Int. J. Biochem. Cell Biol. 2015, 64, 265–276. [Google Scholar] [CrossRef] [PubMed]
  75. Lin, Q.; Gao, Z.; Alarcon, R.M.; Ye, J.; Yun, Z. A role of miR-27 in the regulation of adipogenesis. FEBS J. 2009, 276, 2348–2358. [Google Scholar] [CrossRef] [PubMed]
  76. Raver-Shapira, N.; Marciano, E.; Meiri, E.; Spector, Y.; Rosenfeld, N.; Moskovits, N.; Bentwich, Z.; Oren, M. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 2007, 26, 731–743. [Google Scholar] [CrossRef] [PubMed]
  77. 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]
  78. Montanini, L.; Lazzeroni, P.; Sartori, C.; Nobili, V.; Crafa, P.; Bernasconi, S.; Street, M.E. Mir-146a and-155 are involved in FOXO1 regulation and non alcoholic fatty liver disease in childhood obesity. In Proceedings of European Society For Paediatric Endocrinology, Dublin, Ireland, 18–20 September 2014.
  79. Jiang, W.; Liu, J.; Dai, Y.; Zhou, N.; Ji, C.; Li, X. MiR-146b attenuates high-fat diet-induced non-alcoholic steatohepatitis in mice. J. Gastroenterol. Hepatol. 2015, 30, 933–943. [Google Scholar] [CrossRef] [PubMed]
  80. Cheung, O.; J Sanyal, A. Role of microRNAs in non-alcoholic steatohepatitis. Curr. Pharm. Design 2010, 16, 1952–1957. [Google Scholar] [CrossRef]
  81. Miller, A.M.; Gilchrist, D.S.; Nijjar, J.; Araldi, E.; Ramirez, C.M.; Lavery, C.A.; Fernandez-Hernando, C.; McInnes, I.B.; Kurowska-Stolarska, M. MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice. PLoS ONE 2013, 8, e72324. [Google Scholar] [CrossRef] [PubMed]

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Zarfeshani, A.; Ngo, S.; Sheppard, A.M. MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH. J. Clin. Med. 2015, 4, 1938-1950.

AMA Style

Zarfeshani A, Ngo S, Sheppard AM. MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH. Journal of Clinical Medicine. 2015; 4(11):1938-1950.

Chicago/Turabian Style

Zarfeshani, Aida, Sherry Ngo, and Allan M. Sheppard. 2015. "MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH" Journal of Clinical Medicine 4, no. 11: 1938-1950.

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