Next Article in Journal
Role of Hibernation Promoting Factor in Ribosomal Protein Stability during Pseudomonas aeruginosa Dormancy
Next Article in Special Issue
Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure
Previous Article in Journal
Genome-Wide Identification of the Expansin Gene Family and Its Potential Association with Drought Stress in Moso Bamboo
Previous Article in Special Issue
A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and “Medical Cannabinoids”
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 24
10.3390/ijms21249493
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease

by
David E. Stec
1,* and
Terry D. Hinds, Jr.
2,*
1
Department of Physiology & Biophysics, Center for Cardiovascular and Metabolic Diseases Research, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
2
Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(24), 9493; https://doi.org/10.3390/ijms21249493
Submission received: 12 November 2020 / Revised: 7 December 2020 / Accepted: 9 December 2020 / Published: 14 December 2020
(This article belongs to the Special Issue Natural, Semi-Synthetic and Synthetic Compounds Acting on Heme Oxygenase System)
Browse Figure
Review Reports Versions Notes

Abstract

:
Heme oxygenase (HO) is a critical component of the defense mechanism to a wide variety of cellular stressors. HO induction affords cellular protection through the breakdown of toxic heme into metabolites, helping preserve cellular integrity. Nonalcoholic fatty liver disease (NAFLD) is a pathological condition by which the liver accumulates fat. The incidence of NAFLD has reached all-time high levels driven primarily by the obesity epidemic. NALFD can progress to nonalcoholic steatohepatitis (NASH), advancing further to liver cirrhosis or cancer. NAFLD is also a contributing factor to cardiovascular and metabolic diseases. There are currently no drugs to specifically treat NAFLD, with most treatments focused on lifestyle modifications. One emerging area for NAFLD treatment is the use of dietary supplements such as curcumin, pomegranate seed oil, milk thistle oil, cold-pressed Nigella Satvia oil, and resveratrol, among others. Recent studies have demonstrated that several of these natural dietary supplements attenuate hepatic lipid accumulation and fibrosis in NAFLD animal models. The beneficial actions of several of these compounds are associated with the induction of heme oxygenase-1 (HO-1). Thus, targeting HO-1 through dietary-supplements may be a useful therapeutic for NAFLD either alone or with lifestyle modifications.

1. Introduction

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic levels in the United States in the patient population, where it has had a profound effect on the healthcare system [1,2,3]. NAFLD is characterized by hepatic lipid accumulation and insulin resistance that, when coupled with increased inflammation and oxidative stress, can lead to nonalcoholic steatohepatitis (NASH), liver fibrosis, or liver cancer [1]. NAFLD is also associated with a greater risk of cardiovascular disease; however, the mechanism by which NAFLD enhances this risk is not known [1,2,4]. It is becoming recognized that NAFLD is a complex phenotype, as evidenced by the wide spectrum of disease severity as well as the wide variability in the patient presentation of the disease. It has been suggested that NAFLD progresses through multiple “hits” which couple insulin resistance and alterations in adipose tissue lipolysis with increasing efflux of free fatty acids from adipose to the liver resulting in hepatic steatosis. Given this propensity of NAFLD to occur with obesity and other metabolic disorders, renaming the disease metabolic dysfunction-associated fatty liver disease (MAFLD) has recently been proposed [5,6]. Hepatic steatosis makes the liver vulnerable to additional “hits” such as inflammation and increased oxidative stress resulting in hepatocyte injury and disease progression.
Heme oxygenase (HO) is the rate-limiting enzyme responsible for the breakdown of heme into biliverdin, carbon monoxide, and free heme [7]. Biliverdin reductase reduces biliverdin to bilirubin, and ferritin sequesters the free heme released by HO. Heme is a known generator of cellular oxidative stress but also plays an important role in numerous cellular functions. Heme is a ligand of nuclear receptors of the REV-ERB (α and B) family, where it regulates such processes such as circadian rhythms, metabolism, and immune function [8,9,10]. The HO isozymes are present in two isoforms, HO-1, which is inducible by a wide variety of stimuli, including hypoxia, oxidative stress, exposure to toxins, and natural products [11,12], and HO-2, which is the constitutively expressed isoform. Chemical induction or genetic overexpression of HO-1 protects against numerous cardiovascular diseases such as hypertension, stroke, atherosclerosis, and kidney disease [13,14,15,16,17,18,19]. Human patients with a deficiency in HO-1 present with severe hemolysis, inflammation, and ectopic iron deposition, similar to the phenotypes described in HO-1 null mice [20,21,22,23]. Recent studies have revealed several natural herbal supplements improve NAFLD and metabolic dysfunction, which might be mediated by their induction of HO-1. We discuss these further and the impact that herbal supplements that induce HO-1 may have in relieving the metabolic distress to alleviate the cost burden on the healthcare system.

2. Heme Oxygenase and Hepatic Steatosis

Alterations in hepatic HO levels profoundly affect hepatic steatosis in several rodent models of fatty liver [24,25,26,27]. The most commonly studied method for inducing HO-1 has been with cobalt protoporphyrin IX (CoPP), which is thought to inactivate the BTB domain and CNC homolog 1 (BACH1) transcription factor that inhibits Hmox1 gene activity [28]. CoPP increases mRNA and protein levels that also equates to higher HO activity measured by higher bilirubin levels [24,29]. Other metal-containing metalloprotoporphyrins can also increase HO-1 expression. However, some increase expression but inhibit activity, such as tin protoporphyrin IX (SnPP) and stannic mesoporphyrin (SnMP). These are the most common pharmacological agonist of HO activity (CoPP) and antagonists (SnMP and SnPP). Studies in obese leptin-deficient (ob/ob) mice treated with CoPP or SnMP showed that both increased HO-1 expression [24]. However, only CoPP decreased plasma heme and increased serum bilirubin levels, which are indicators of raised HO activity. The CoPP-induction of HO activity reduced body weight and blood glucose, as well as improved NAFLD and hepatic glycogen content [24]. These indicate that increasing HO activity may have metabolic protection that could be useful for treating these disorders.
Both chemical and genetic induction of HO-1 reduces hepatic steatosis in Zucker fatty rats and mice fed high fat or methionine-choline deficient (MCD) diet [24,25,26]. Hepatic induction of HO-1 reduces not only hepatic steatosis but also decreases inflammatory factors such as suppressor of cytokine signaling-1, interleukin-6, and tumor necrosis factor-alpha (Figure 1). HO-1 induction also decreases hepatic macrophage-chemoattractant-protein-1 (MCP-1), with similar reductions in the pro-inflammatory M1-phenotype marker, Anti-Macrophages/Monocytes Antibody, clone ED-1, and resulting in decreased infiltration of hepatic macrophages [25,26]. Likewise, HO-1 induction concomitantly potentiates the protein expression of anti-inflammatory macrophage-M2-markers, including CD-206, ED2, and interleukin-10 (IL-10) [26]. One of the biggest challenges in treating obesity is reducing the chronic-low-grade inflammation associated [30].
HO-1 induction not only modifies the inflammatory response in the liver but also alters the level of several genes involved in hepatic fatty acid metabolism, such as fatty acid synthase (FAS) and peroxisome proliferator-activated receptor-α (PPARα) (Figure 1) [24]. Hepatic HO-1 induction also increases fibroblast growth factor-21 (FGF21) levels [24]. FGF21 is an important metabolic hormone that improves insulin sensitivity and decreases hepatic steatosis [31]. HO-1 increases PPARα and FGF21 through enhanced production of bilirubin. Recent studies have identified bilirubin as a novel selective PPARα modulator (SPPARM) [32,33]. Bilirubin is able to alter specific transcriptional coregulators when it is bound to PPARα as a ligand, which increases the levels of PPARα-target genes [32,34,35]. Thus, the effect of HO-1 induction to alter PPARα and its target genes like FGF21 is likely due to enhanced bilirubin production. The bilirubin induction of FGF21 was confirmed to be by PPARα in global PPARα knockout mice treated with bilirubin, which showed no change in expression, but wild-type control mice treated with bilirubin did have higher FGF21 [32]. Later studies confirmed that direct PPARα-bilirubin binding by fluorescent competitive ligand-binding assays [34]. The study also showed by chromatin immunoprecipitation (ChIP) assays that PPARα was enriched at gene promoters and that coregulator recruitment to purified mouse and human PPARα protein was enhanced by treatment with bilirubin [34]. Another study showed an extensive analysis using RNA-sequencing in human HepG2 hepatocytes with lentiviral shRNA knockdown of PPARα that ~95% of bilirubin-controlled gene activity is PPARα-dependent [36]. Treatment of mice with obesity-induced NAFLD with bilirubin nanoparticles reduced hepatic steatosis and improved liver function, lowering AST liver dysfunction marker [35], suggesting that HO-1 protection against NALFD may be mediated by bilirubin. HO production of bilirubin may serve a hormonal function by the actions of bilirubin directly binding and activating the PPARα nuclear receptor transcription factor [37].
Inhibition of HO activity results in increased hepatic lipid accumulation and fibrosis in both animal and cell culture models of NAFLD [25,27]. Inhibition of HO-1 also lowers serum FGF21 levels and reduces the levels of PPARα-target genes in the liver [24]. One mechanism by which blockade of hepatic HO-1 results in enhanced lipid accumulation and fibrosis is through increases in reactive oxygen species (ROS) levels. Enhanced ROS production and reduced antioxidant capacity are emerging areas that have been demonstrated to contribute to enhanced lipid accumulation and fibrosis [38,39,40,41]. Raffaele et al. have shown that epoxyeicosatrienoic intervention increases HO-1- PGC1α-mitochondrial signaling to improve NAFLD in obese mice [42]. The HO-1 activation leads to increased bilirubin-PPARα stimulation, which has also been shown to improve mitochondrial function [34]. Mainly since the loss of hepatic PPARα induces NALFD, which worsens on a high-fat diet [43], these suggest that diet modification with HO-1 induction may have synergism that further improves NAFLD. Also, the inclusion of exercise may benefit this regimen as rats with high aerobic running capacity have been shown to have significantly higher bilirubin levels [44].
The regulation of HO-1 gene transcription occurs through a combination of transcription factors like nuclear factor (erythroid-derived 2)-like-2 (Nrf2), which increases HO-1 levels as well as BACH1, which suppresses HO-1 transcription. BACH1 competes with Nrf2 for binding to the Maf recognition elements (MAREs) in the HO-1 promoter [45,46]. Studies in cultured liver cells demonstrated that inhibition of BACH1 levels with specifically targeted siRNAs increases HO-1 levels [47]. Mice that were genetically deficient in BACH1 exhibit reduced levels of hepatic steatosis and preserved levels of PPARα in a methionine-choline deficient (MCD) diet model of NAFLD [48]. DHA (docosahexaenoic acid) is an omega-3 fatty acid contained in high levels in several species of cold-water fish. DHA has a positive effect on a wide variety of diseases such as adult-onset diabetes mellitus, arthritis, atherosclerosis, depression, hypertension, myocardial infarction, and thrombosis. Studies by Wang et al. demonstrated that DHA attenuates BACH1 binding to the Antioxidant Response Elements (AREs) in the HO-1 gene promoter by reducing nuclear BACH1 protein expression by promoting its degradation [49]. In addition, DHA enhances HO-1 gene transcription through Nrf2 binding to the AREs independent of nuclear Nrf2 expression levels [49]. Thus, targeting HO-1 transcriptional repressors such as BACH1 could be a novel therapeutic approach for NAFLD treatment.
Natural product induction of Nrf2 is another mechanism that may be protective against NAFLD. Mice lacking Nrf2 are highly susceptible to the development of NASH when they are challenged with a methionine- and choline-deficient (MCD) diet. Nrf2 deficient mice showed a substantial increase in hepatic steatosis, hepatic oxidative stress, an increase in hepatic NF-kappaB p65 protein, and an increase in inflammatory markers tumor necrosis factor-α (TNFα), cyclooxygenase 2, and inducible nitric oxide synthase as compared to livers from wild-type mice [50]. These results are in contrast with results from hepatocyte-specific Nrf2 knockout mice place on a high-fat diet. In these mice, the reduction in the levels of peroxisome proliferator-activated receptor γ (PPARγ) and its target lipogenic genes resulted in the attenuation of high-fat diet-induced hepatic steatosis and inflammation [51]. In separate studies, hepatocyte-specific Nrf2 KO mice fed a HFD exhibited improved insulin sensitivity, lower insulin levels and no significant liver triglyceride accumulation [52]. Interestingly, adipocyte-specific knockout of Nrf2 resulted in several metabolic abnormalities including glucose intolerance, high fasting glucose levels, and alteration in plasma fatty acids and cholesterol [52]. The results from the tissue-specific Nrf2 KO studies demonstrate the complex interactions of loss of Nrf2 from different tissues and suggest that specific targeting of Nrf2 in selective tissues may be required to improve metabolic abnormalities associated with diseases like obesity and NAFLD [53]. Studies with natural Nrf2 inducers such as sulforaphane and its precursor glucoraphanin as well as glycycoumarin (GCM) which is a representative coumarin compound in licorice have demonstrated the hepatoprotective effects of these compounds in both models of NAFLD as well as NASH [54,55]. These products induce Nrf2 to improve antioxidant defense, stimulate 5’ AMP-activated protein kinase (AMPK)-mediated energy homeostasis, induce autophagy degradation process, and improve mitochondrial dysfunction. Additional studies in Nrf2 deficient animals are needed in order to determine if these products act through pathways independent of Nrf2 to protect against NAFLD.

3. Natural Product HO-1 Inducers and NAFLD

3.1. Curcumin

Curcumin, the bioactive component found in the spice turmeric, has a long tradition in Eastern medicine where it has been used as an anti-inflammatory and antioxidant agent [56]. Curcumin is a potent inducer of HO-1 in the liver [57,58]. Both curcumin or a more bioavailable derivative, pegylated curcumin, have been demonstrated to attenuate the development of NAFLD and the progression to NASH in animal models [59,60]. Curcumin supplementation protects against NAFLD via several distinct mechanisms. Curcumin has potent anti-inflammatory properties through attenuation of markers of inflammation, such as elevated C-reactive protein (CRP) and interleukin-6 (IL-6) levels [61]. Curcumin can also act through the Nfr2/FXR/LXRalpha pathway to regulate the expression of CYP3A and CYP7A as well as alter the expression of CD36, sterol regulatory element-binding protein-1c (SREBP-1c), and FAS to regulate cholesterol and fatty acid metabolism in NAFLD [62]. Hepatic proteomic analysis in methionine and choline-deficient (MCD) mice supplemented with curcumin revealed inhibition of O-linked beta-N-acetylglucosamine (O-GlcNAc) modifications resulting in the attenuation of nuclear factor-kappaB (NF-kappaB) in inflammation signaling [63].
While the data regarding the effectiveness of curcumin supplementation in protection against the development and progression of NAFLD in preclinical models are encouraging, the translation of these results has not been consistent (Table 1). Recent meta-analyses of 8–9 randomized controlled trials found a positive effect of curcumin supplementation on liver enzymes, serum cholesterol, serum insulin and HOMA-IR, and waist circumference in patients with NAFLD [64,65]. However, several clinical trials directly examining the effectiveness of curcumin supplementation in NAFLD patients have not found any significant benefit for curcumin supplementation. Saadati et al. examined the effects of curcumin supplementation on inflammatory and hepatic fibrosis markers in 50 NAFLD patients and failed to document any improvement in hepatic steatosis or fibrosis with curcumin supplementation [66]. Likewise, a similar study examining the effect of curcumin supplementation on DNA damage caused by increased oxidative stress in NAFLD patients failed to demonstrate any significant protective effect of curcumin supplementation [67]. Lastly, a mixture of natural ingredients, including curcumin, could not document any significant beneficial effect on liver enzymes or metabolic and inflammatory variables in NAFLD patients [68]. The beneficial effects of curcumin supplementation in animal models of NAFLD have yet to be fully observed in clinical trials of NAFLD patients. Clinical trials better designed with different formulations of curcumin [60] may be needed in order to determine if curcumin supplementation is beneficial for NAFLD patients.

3.2. Pomegranate Seed Oil

Pomegranates and pomegranate seed oil may be beneficial for combating obesity since they contain numerous antioxidants such as ascorbic acid, polyphenols, punicic acid and tannins [85]. Pomegranate seed oil (PSO) contains a dense fraction of these antioxidants and is preferable to pomegranate juice, which contains high levels of sugars such as fructose (6.83/100 g) and glucose (6.66/100 g) [86]. The sugars in pomegranate juice such as fructose have been demonstrated to induce obesity, resulting in inflammatory and oxidative stress, both of which promote NAFLD and metabolic syndrome [87]. The high level of sugars found in pomegranate juice may be responsible for the lack of effect on insulin secretion and sensitivity in a clinical trial of patients with obesity [88]. PSO has a greater therapeutic potential because it lacks the sugars found in pomegranate juice and contains more natural antioxidant compounds.
Studies in mouse models of high-fat diet-induced obesity have demonstrated a protective effect of pomegranate seed oil (PSO) on weight gain and body composition [69,70]. PSO supplementation also improved insulin sensitivity in the periphery but did not have any effect on improving liver insulin sensitivity [69,70]. In a double-blind, placebo-controlled, randomized, 16 week clinical study of non-diabetic, obese premenopausal women with and without NAFLD, PSO mixed with brown marine algae fucoxanthin resulted in a significant reduction of body weight, liver fat content, liver enzymes, serum triglycerides, and C-reactive protein in the NAFLD group [71]. A recent study in a mouse model of high-fat diet-induced obesity and NAFLD demonstrated that PSO supplementation reduced hepatic steatosis and fibrosis, improved hepatic mitochondrial function as well as decreasing fasting glucose levels [72]. The improved hepatic steatosis and insulin sensitivity was due to an upregulation of hepatic HO-1 by PSO supplementation [72]. Hepatic HO-1 induction also resulted in an increase in mitofusin-2 (Mfn2), mitochondrial dynamin like GTPase (OPA-1), PR domain containing 16 (PRDM 16), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) levels as well as the upregulation of hepatic insulin receptor phosphorylation [72]. These effects of HO-1 induction on PGC1α levels in the liver are similar to those observed in the heart [89]. However, the importance of HO-1 induction to the beneficial effects of PSO needs to be evaluated in future studies (Table 1).

3.3. Milk Thistle Seed Oil

The milk thistle plant (Silybum marianum) can be processed using several methods, that include ethanol extraction and cold pressing to make milk thistle oil (MTO). MTO contains various polyphenols such as, p-coumaric, vanillic acid, and silybin as well a high levels of α-tocopherol [90,91]. Ethanol extraction of milk thistle increases the level of silymarin. Silymarin treatment protects against chemical-induced liver injury as well as numerous liver diseases associated with increased levels of oxidative stress and hepatic steatosis [92,93]. Recently, Pais et al. demonstrated the protective effects of a patented extract of milk thistle (ETHIS-094) in a mouse model of NAFLD to NASH progression [73].
Isolated silymarin flavonoids, 2,3-dehydrosilybins A and B decrease lipoperoxidation in the liver through downregulation of hepatic UGT1A1 and subsequent increases in hepatic and plasma bilirubin levels [94]. Thus, it appears that increases in serum bilirubin levels could mediate some of the hepato-protective effects of silymarin. Bilirubin protects against the development of NAFLD in both animal models and human patient populations [95,96,97,98,99]. Bilirubin can protect the liver by acting as a hormone capable of activating nuclear receptors such as PPARα, which can increase the expression of genes that regulate hepatic β-oxidation [32,33,100].
MTO contains very little silymarin when extracted as a cold press oil; however, it retains its polyphenols, free fatty acids, and other natural antioxidants which can be beneficial in the context of NAFLD. MTO is a potent inducer of HO-1 in both adipose tissue and liver [74]. MTO supplementation in dietary-induced obese mice prevented several of the cardiovascular and metabolic pathologies in dietary obesity such as excessive weight gain, hyperglycemia, and hypertension and also decreased obesity-induced hepatic fibrosis through decreases in matrix metalloproteinase-2 (MMP2) and 9 [74]. Inflammation is very prevalent in obesity and drives cardiovascular and metabolic diseases associated with obesity [101]. MTO supplementation decreased obesity-induced hepatic inflammation through the down-regulation of several critical inflammatory mediators such as nephroblastoma overexpressed (NOV), TWIST, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [74]. MTO also improved hepatic insulin signaling through increases in PGC-1α and the activation of the β subunit of the insulin receptor (IR) [74]. MTO supplementation attenuates many of the complications associated with obesity and could prove to be a novel dietary treatment for obesity and its cardiovascular and metabolic complications (Table 1).

3.4. Cold Pressed Nigella Sativa Oil

Nigella Sativa (N.Sativa) is an annual flowering plant with a long history of medicinal use, especially in the Middle Eastern Mediterranean region. The seeds of N. sativa contain thymoquinone (TQ) which are present at high levels in essential oils derived from the seeds. N. sativa oil and are protective in several different models of liver injury, including aluminum chloride-induced injury, carbon tetrachloride (CCL4) induced liver injury, and carboplatin-induced liver damage [102,103,104]. N. sativa oil supplementation decreases serum markers of liver injury such as aspartate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase. Increased levels of oxidative stress are typical hallmarks of all of these different hepatotoxic chemicals, and N. sativa oil supplementation was able to decrease reactive oxygen species levels as well as boost the levels of antioxidants such as glutathione peroxidase and superoxide dismutase [102,103,104].
N. sativa oil and TQ are potent inducers of HO-1 in the lung, heart, liver, and cell lines such as HaCaT cells derived from human keratinocytes [75,76,105,106,107]. Recent studies have demonstrated that supplementation of TQ alone or given in combination with fish oil omega-3 prevents the development of dietary obesity-induced NAFLD [75,76]. TQ alone or in combination, also alleviated other dietary-induced obesity complications such as hypertension, decreases in oxygen consumption, and insulin resistance [75,76]. The ability of TQ supplementation to lower blood pressure in dietary-induced obesity is similar to a previous study demonstrating the antihypertensive actions of TQ supplementation in a model of nitric oxide deficient hypertension [106]. TQ supplementation also restored the levels of important markers of mitochondrial functions such as mitofusin-1 (MFN-1), MFN-2, and OPA1 in the liver [75,76]. Dietary obesity also induced hepatic fibrosis and inflammation, both of which were significantly reversed by TQ supplementation [75,76]. TQ supplementation also increased hepatic Akt signaling leading to alterations in insulin receptor phosphorylation and liver insulin resistance improvements [76]. Rashidmayvan et al. recently tested the effectiveness of N. sativa oil in NAFLD patients in an eight week randomized, double-blind, placebo-controlled clinical trial [77]. Reductions in fasting blood glucose, lipid profiles (TG, TC, LDL, VLDL), liver enzymes (aspartate transaminase (AST) and alanine transaminase (ALT)), and inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), were found as a result of consumption of NS seed oil [77]. NS see oil also increased HDL levels, compared to the placebo group [77]. Thus, it appears that N. sativa oil either by itself or used besides other dietary supplements such as omega-3 fish oil may help protect against NAFLD in human patient populations. Further studies are needed to determine the specific role of HO-1 induction in the protection afforded by N. sativa oil supplementation (Table 1).

3.5. Resveratrol

Resveratrol is a phytoalexin, a class of compounds produced by many plants and is found in high levels in red wine due to the fact that this type of wine is often fermented with the skins of the grapes, which contain high levels of resveratrol. Resveratrol is also found in berries, including blueberries, raspberries, mulberries, cranberries, and bilberries. Resveratrol induces HO-1 in the brain, heart, kidney, and liver. In the brain, resveratrol induces HO-1 to protect against ischemic stroke [108,109]. Resveratrol also protects the heart in models of diabetic-induced cardiomyopathy as well as ischemia-reperfusion injury [110,111]. Resveratrol induces HO-1 through activation of the Nrf2 pathway in both cultured PC12 cells and in Hep G2 liver cells through activation of the extracellular signal-regulated kinase (ERK) pathway [112,113]. Resveratrol also acts epigenetically to alter methylation of the Nrf2 promoter in the liver as treatment of HepG2 cells with 5-aza, a demethylating agent, prevents resveratrol induced Nfr2 gene induction and subsequent increases in HO-1 [114].
Resveratrol exerts protective effects in numerous preclinical models of NAFLD through a variety of mechanisms. Zucker fatty rats treated with resveratrol for six weeks demonstrated decreased liver weight and triglyceride content [78]. Resveratrol treatment also reduced hepatic oxidative stress and increased hepatic carnitine palmitoyltransferase-Ia (CPT-Ia) and acyl-coenzyme A oxidase (ACO) activity [78]. In a rat model of dietary-induced NAFLD, resveratrol treatment decreased NAFLD severity through decreases in inflammatory cytokines such as TNFα, and through increases in superoxide dismutase, glutathione peroxidase, and catalase [79]. In Hep G2 hepatocytes, resveratrol treatment has been demonstrated to have a profound effect on gene expression upregulating the expression of Sirt1 and forkhead box O1 (FOXO1), and downregulating the expression of sterol regulatory element-binding protein1 (SREBP1) [80]. In separate studies, Izdebska et al. demonstrated that resveratrol treatment alleviated high glucose-induced steatosis through increases in mitochondrial activity [81]. Selective targeting of hepatocytes for gene delivery can be achieved with molecules that recognize and bind to receptors specifically found on the surface of hepatocytes. One class of molecules that can be used for hepatocyte-specific targeting are asialoglycoprotein receptors (ASGPR). ASGPRs are receptors overexpressed in hepatic parenchymal cells and not expressed in non-hepatic cells. A recent study delivered resveratrol in vivo by utilization of lysozyme micelles (Lys M) coated with D- (+) galactose (Gal) conjugated to an oxidized starch (Gal-OS) polymer [82]. The targeted resveratrol attenuated hepatic steatosis and improved hepatic insulin sensitivity in dietary-induced obese NAFLD mice through modulation of AMPK/SIRT1/FAS/SREBP1c signaling pathway [82]. Resveratrol has also been used in combination with another natural product, HO-1 inducer, curcumin, to protect against high fat diet-induced NAFLD [115]. Resveratrol supplementation, in addition to exercise training, improved hepatic steatosis, and decreased hepatic inflammation, and increased antioxidant capacity in the liver [116].
Clinical trials of resveratrol supplementation have not been as promising as those of preclinical models (Table 1). In small randomized, placebo-controlled clinical trials of NAFLD and control patients, resveratrol supplementation had minimal effect on hepatic steatosis, insulin sensitivity, plasma markers of inflammation, and antioxidants [83,84]. Kantartzis et al. reported in a large randomized, placebo-controlled clinical trial with over 100 NAFLD patients that resveratrol supplementation failed to have any measurable effect on hepatic steatosis or other cardiometabolic risk factors [117]. A similar study on a smaller group of patients was unable to find any protective effect of resveratrol supplementation on atherogenic indices and blood pressure in patients with NAFLD [118]. Likewise, results from several meta-analysis studies examining the effectiveness of resveratrol supplementation in NAFLD patients failed to support resveratrol in the management of NAFLD and its metabolic and cardiovascular complications [119,120]. Overall, while the data supporting the beneficial effects of resveratrol in NAFLD treatment in preclinical models is strong, clinical trials have not shown similar promise. It is possible that resveratrol could prove to be beneficial to NAFLD patients when used in concert with other natural products or with lifestyle modifications.

4. Conclusions

In NAFLD, levels of HO-1 are decreased, possibly through alterations in the levels of BACH1, leading to increased ROS production and inflammation, both of which contribute to enhanced triglyceride storage and reductions in glycogen (Figure 1). Natural product HO-1 inducers like curcumin, PSO, MTO, N. sativa oil, and resveratrol activate HO-1 expression to reduce ROS production and inflammation. Activation of HO-1 also stimulates PPARα, which results in the burning of hepatic fatty acids and increases in glycogen storage. HO-1 induction also plays a key role in the transition of macrophages from the inflammatory M1 phenotype into the anti-inflammatory M2 [121,122]. Whether used alone or in combination with other dietary supplements or medications, natural product HO-1 inducers may represent novel treatment options for patients most at risk for developing NAFLD and its complications.

Author Contributions

D.E.S. and T.D.H.J. conceived, designed, and drafted the manuscript. TDH produced the graphic illustrations. Both authors edited the manuscript and gave the final approval for publication. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Institutes of Health 1R01DK121797 (T.D.H.J.) and 1R01DK126884 (D.E.S.), the National Heart, Lung, and Blood Institute K01HL125445 (T.D.H.J.) and P01HL0519711 (D.E.S.), and the National Institute of General Medical Sciences P20GM104357 (D.E.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 2018, 24, 908–922. [Google Scholar] [CrossRef] [PubMed]
  2. Muthiah, M.D.; Sanyal, A.J. Burden of Disease due to Nonalcoholic Fatty Liver Disease. Gastroenterol. Clin. North. Am. 2020, 49, 1–23. [Google Scholar] [CrossRef] [PubMed]
  3. Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Baratta, F.; Pastori, D.; Angelico, F.; Balla, A.; Paganini, A.M.; Cocomello, N.; Ferro, D.; Violi, F.; Sanyal, A.J.; Del Ben, M. Nonalcoholic Fatty Liver Disease and Fibrosis Associated with Increased Risk of Cardiovascular Events in a Prospective Study. Clin. Gastroenterol. Hepatol. 2020, 18, 2324–2331. [Google Scholar] [CrossRef] [PubMed]
  5. Eslam, M.; Sanyal, A.J.; George, J.; International Consensus, P. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020, 158, 1999–2014 e1991. [Google Scholar] [CrossRef] [PubMed]
  6. Eslam, M.; Newsome, P.N.; Sarin, S.K.; Anstee, Q.M.; Targher, G.; Romero-Gomez, M.; Zelber-Sagi, S.; Wai-Sun Wong, V.; Dufour, J.F.; Schattenberg, J.M.; et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol. 2020, 73, 202–209. [Google Scholar] [CrossRef]
  7. Hosick, P.A.; Stec, D.E. Heme oxygenase, a novel target for the treatment of hypertension and obesity? Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 302, R207–R214. [Google Scholar] [CrossRef] [Green Version]
  8. Duvigneau, J.C.; Esterbauer, H.; Kozlov, A.V. Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways. Antioxidants 2019, 8, 475. [Google Scholar] [CrossRef] [Green Version]
  9. Raghuram, S.; Stayrook, K.R.; Huang, P.; Rogers, P.M.; Nosie, A.K.; McClure, D.B.; Burris, L.L.; Khorasanizadeh, S.; Burris, T.P.; Rastinejad, F. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat. Struct Mol. Biol. 2007, 14, 1207–1213. [Google Scholar] [CrossRef] [Green Version]
  10. Duvigneau, J.C.; Piskernik, C.; Haindl, S.; Kloesch, B.; Hartl, R.T.; Huttemann, M.; Lee, I.; Ebel, T.; Moldzio, R.; Gemeiner, M.; et al. A novel endotoxin-induced pathway: Upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction. Lab. Invest. 2008, 88, 70–77. [Google Scholar] [CrossRef] [Green Version]
  11. Abraham, N.G.; Kappas, A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol. Rev. 2008, 60, 79–127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Abraham, N.G.; Kappas, A. Heme oxygenase and the cardiovascular-renal system. Free Radic. Biol. Med. 2005, 39, 1–25. [Google Scholar] [CrossRef]
  13. Sacerdoti, D.; Escalante, B.; Abraham, N.G.; McGiff, J.C.; Levere, R.D.; Schwartzman, M.L. Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats. Science 1989, 243, 388–390. [Google Scholar] [CrossRef] [PubMed]
  14. Levere, R.D.; Martasek, P.; Escalante, B.; Schwartzman, M.L.; Abraham, N.G. Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. J. Clin. Investig. 1990, 86, 213–219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Sabaawy, H.E.; Zhang, F.; Nguyen, X.; ElHosseiny, A.; Nasjletti, A.; Schwartzman, M.; Dennery, P.; Kappas, A.; Abraham, N.G. Human heme oxygenase-1 gene transfer lowers blood pressure and promotes growth in spontaneously hypertensive rats. Hypertension 2001, 38, 210–215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Vera, T.; Kelsen, S.; Stec, D.E. Kidney-specific induction of heme oxygenase-1 prevents angiotensin II hypertension. Hypertension 2008, 52, 660–665. [Google Scholar] [CrossRef] [Green Version]
  17. Stec, D.E.; Drummond, H.A.; Gousette, M.U.; Storm, M.V.; Abraham, N.G.; Csongradi, E. Expression of heme oxygenase-1 in thick ascending loop of henle attenuates angiotensin II-dependent hypertension. J. Am. Soc. Nephrol. 2012, 23, 834–841. [Google Scholar] [CrossRef] [Green Version]
  18. Panahian, N.; Yoshiura, M.; Maines, M.D. Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J. Neurochem. 1999, 72, 1187–1203. [Google Scholar] [CrossRef]
  19. Juan, S.H.; Lee, T.S.; Tseng, K.W.; Liou, J.Y.; Shyue, S.K.; Wu, K.K.; Chau, L.Y. Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2001, 104, 1519–1525. [Google Scholar] [CrossRef] [Green Version]
  20. Yachie, A.; Koizumi, S. Heme oxygenase 1 deficiency. Ryoikibetsu Shokogun Shirizu 2001, 796–797. [Google Scholar]
  21. Kawashima, A.; Oda, Y.; Yachie, A.; Koizumi, S.; Nakanishi, I. Heme oxygenase-1 deficiency: The first autopsy case. Hum. Pathol. 2002, 33, 125–130. [Google Scholar] [CrossRef] [PubMed]
  22. Radhakrishnan, N.; Yadav, S.P.; Sachdeva, A.; Pruthi, P.K.; Sawhney, S.; Piplani, T.; Wada, T.; Yachie, A. Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. J. Pediatr. Hematol. Oncol. 2011, 33, 74–78. [Google Scholar] [CrossRef] [PubMed]
  23. Poss, K.D.; Tonegawa, S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl. Acad. Sci. USA 1997, 94, 10919–10924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Hinds, T.D., Jr.; Sodhi, K.; Meadows, C.; Fedorova, L.; Puri, N.; Kim, D.H.; Peterson, S.J.; Shapiro, J.; Abraham, N.G.; Kappas, A. Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21. Obesity (Silver Spring) 2014, 22, 705–712. [Google Scholar] [CrossRef] [Green Version]
  25. Wang, R.Q.; Nan, Y.M.; Wu, W.J.; Kong, L.B.; Han, F.; Zhao, S.X.; Kong, L.; Yu, J. Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice. Lipids Health Dis. 2011, 10, 31. [Google Scholar] [CrossRef] [Green Version]
  26. Salley, T.N.; Mishra, M.; Tiwari, S.; Jadhav, A.; Ndisang, J.F. The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes. PLoS ONE 2013, 8, e79270. [Google Scholar] [CrossRef]
  27. Raffaele, M.; Carota, G.; Sferrazzo, G.; Licari, M.; Barbagallo, I.; Sorrenti, V.; Signorelli, S.S.; Vanella, L. Inhibition of Heme Oxygenase Antioxidant Activity Exacerbates Hepatic Steatosis and Fibrosis In Vitro. Antioxidants 2019, 8, 277. [Google Scholar] [CrossRef] [Green Version]
  28. Sun, J.; Hoshino, H.; Takaku, K.; Nakajima, O.; Muto, A.; Suzuki, H.; Tashiro, S.; Takahashi, S.; Shibahara, S.; Alam, J.; et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 2002, 21, 5216–5224. [Google Scholar] [CrossRef]
  29. Vanella, L.; Sodhi, K.; Kim, D.H.; Puri, N.; Maheshwari, M.; Hinds, T.D., Jr.; Bellner, L.; Goldstein, D.; Peterson, S.J.; Shapiro, J.I.; et al. Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade. Stem Cell Res. Ther. 2013, 4, 28. [Google Scholar] [CrossRef] [Green Version]
  30. Monteiro, R.; Azevedo, I. Chronic inflammation in obesity and the metabolic syndrome. Mediat. Inflamm. 2010, 2010. [Google Scholar] [CrossRef]
  31. Xu, J.; Lloyd, D.J.; Hale, C.; Stanislaus, S.; Chen, M.; Sivits, G.; Vonderfecht, S.; Hecht, R.; Li, Y.S.; Lindberg, R.A.; et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009, 58, 250–259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Stec, D.E.; John, K.; Trabbic, C.J.; Luniwal, A.; Hankins, M.W.; Baum, J.; Hinds, T.D., Jr. Bilirubin Binding to PPARalpha Inhibits Lipid Accumulation. PLoS ONE 2016, 11, e0153427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Hinds, T.D., Jr.; Stec, D.E. Bilirubin, a Cardiometabolic Signaling Molecule. Hypertension 2018, 72, 788–795. [Google Scholar] [CrossRef] [PubMed]
  34. Gordon, D.M.; Neifer, K.L.; Hamoud, A.A.; Hawk, C.F.; Nestor-Kalinoski, A.L.; Miruzzi, S.A.; Morran, M.P.; Adeosun, S.O.; Sarver, J.G.; Erhardt, P.W.; et al. Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor alpha. J. Biol. Chem. 2020, 295, 9804–9822. [Google Scholar] [CrossRef] [PubMed]
  35. Hinds, T.D., Jr.; Creeden, J.F.; Gordon, D.M.; Stec, D.F.; Donald, M.C.; Stec, D.E. Bilirubin nanoparticles reduce diet-induced hepatic steatosis, improve fat utilization, and increase plasma β-hydroxybutyrate. Front. Pharmacol. 2020. [Google Scholar] [CrossRef]
  36. Gordon, D.M.; Blomquist, T.M.; Miruzzi, S.A.; McCullumsmith, R.; Stec, D.E.; Hinds, T.D., Jr. RNA-sequencing in human HepG2 hepatocytes reveals PPARalpha mediates transcriptome responsiveness of bilirubin. Physiol. Genom. 2019, 51, 234–240. [Google Scholar] [CrossRef]
  37. Creeden, J.F.; Gordon, D.M.; Stec, D.E.; Hinds, T.D., Jr. Bilirubin as a Metabolic Hormone: The Physiological Relevance of Low Levels. Am. J. Physiol. Endocrinol. Metab. 2020. [Google Scholar] [CrossRef]
  38. Weaver, L.; Hamoud, A.R.; Stec, D.E.; Hinds, T.D., Jr. Biliverdin reductase and bilirubin in hepatic disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2018, 314, G668–G676. [Google Scholar] [CrossRef]
  39. Koek, G.H.; Liedorp, P.R.; Bast, A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin. Chim. Acta. 2011, 412, 1297–1305. [Google Scholar] [CrossRef]
  40. Liu, W.; Baker, S.S.; Baker, R.D.; Zhu, L. Antioxidant Mechanisms in Nonalcoholic Fatty Liver Disease. Curr. Drug Targets 2015, 16, 1301–1314. [Google Scholar] [CrossRef]
  41. Hamoud, A.R.; Weaver, L.; Stec, D.E.; Hinds, T.D., Jr. Bilirubin in the Liver-Gut Signaling Axis. Trends Endocrinol. Metab. 2018, 29, 140–150. [Google Scholar] [CrossRef] [PubMed]
  42. Raffaele, M.; Bellner, L.; Singh, S.P.; Favero, G.; Rezzani, R.; Rodella, L.F.; Falck, J.R.; Abraham, N.G.; Vanella, L. Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1alpha-HO-1-PGC1alpha-mitochondrial signaling. Exp. cell Res. 2019, 380, 180–187. [Google Scholar] [CrossRef]
  43. Stec, D.E.; Gordon, D.M.; Hipp, J.A.; Hong, S.; Mitchell, Z.L.; Franco, N.R.; Robison, J.W.; Anderson, C.D.; Stec, D.F.; Hinds, T.D., Jr. The loss of hepatic PPARalpha promotes inflammation and serum hyperlipidemia in diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 317, R733–R745. [Google Scholar] [CrossRef] [PubMed]
  44. Hinds, T.D., Jr.; Creeden, J.F.; Gordon, D.M.; Spegele, A.C.; Britton, S.L.; Koch, L.G.; Stec, D.E. Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1. Antioxidants 2020, 9, 889. [Google Scholar] [CrossRef] [PubMed]
  45. Kitamuro, T.; Takahashi, K.; Ogawa, K.; Udono-Fujimori, R.; Takeda, K.; Furuyama, K.; Nakayama, M.; Sun, J.; Fujita, H.; Hida, W.; et al. Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. J. Biol. Chem. 2003, 278, 9125–9133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Reichard, J.F.; Sartor, M.A.; Puga, A. BACH1 is a specific repressor of HMOX1 that is inactivated by arsenite. J. Biol. Chem. 2008, 283, 22363–22370. [Google Scholar] [CrossRef] [Green Version]
  47. Shan, Y.; Lambrecht, R.W.; Ghaziani, T.; Donohue, S.E.; Bonkovsky, H.L. Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells: Insights from studies with small interfering RNAS. J. Biol. Chem. 2004, 279, 51769–51774. [Google Scholar] [CrossRef] [Green Version]
  48. Inoue, M.; Tazuma, S.; Kanno, K.; Hyogo, H.; Igarashi, K.; Chayama, K. Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model. J. Clin. Biochem. Nutr. 2011, 48, 161–166. [Google Scholar] [CrossRef] [Green Version]
  49. Wang, S.; Hannafon, B.N.; Wolf, R.F.; Zhou, J.; Avery, J.E.; Wu, J.; Lind, S.E.; Ding, W.Q. Characterization of docosahexaenoic acid (DHA)-induced heme oxygenase-1 (HO-1) expression in human cancer cells: The importance of enhanced BTB and CNC homology 1 (Bach1) degradation. J. Nutr. Biochem. 2014, 25, 515–525. [Google Scholar] [CrossRef] [Green Version]
  50. Chowdhry, S.; Nazmy, M.H.; Meakin, P.J.; Dinkova-Kostova, A.T.; Walsh, S.V.; Tsujita, T.; Dillon, J.F.; Ashford, M.L.; Hayes, J.D. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic. Biol. Med. 2010, 48, 357–371. [Google Scholar] [CrossRef]
  51. Li, L.; Fu, J.; Liu, D.; Sun, J.; Hou, Y.; Chen, C.; Shao, J.; Wang, L.; Wang, X.; Zhao, R.; et al. Hepatocyte-specific Nrf2 deficiency mitigates high-fat diet-induced hepatic steatosis: Involvement of reduced PPARgamma expression. Redox Biol. 2020, 30, 101412. [Google Scholar] [CrossRef] [PubMed]
  52. Chartoumpekis, D.V.; Palliyaguru, D.L.; Wakabayashi, N.; Fazzari, M.; Khoo, N.K.H.; Schopfer, F.J.; Sipula, I.; Yagishita, Y.; Michalopoulos, G.K.; O’Doherty, R.M.; et al. Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice. Am. J. Physiol. Endocrinol. Metab. 2018, 315, E180–E195. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Vasileva, L.V.; Savova, M.S.; Amirova, K.M.; Dinkova-Kostova, A.T.; Georgiev, M.I. Obesity and NRF2-mediated cytoprotection: Where is the missing link? Pharmacol. Res. 2020, 156, 104760. [Google Scholar] [CrossRef] [PubMed]
  54. Xu, L.; Nagata, N.; Ota, T. Impact of Glucoraphanin-Mediated Activation of Nrf2 on Non-Alcoholic Fatty Liver Disease with a Focus on Mitochondrial Dysfunction. Int. J. Mol. Sci. 2019, 20, 5920. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Zhang, E.; Yin, S.; Zhao, S.; Zhao, C.; Yan, M.; Fan, L.; Hu, H. Protective effects of glycycoumarin on liver diseases. Phytother. Res. 2020, 34, 1191–1197. [Google Scholar] [CrossRef]
  56. Pari, L.; Tewas, D.; Eckel, J. Role of curcumin in health and disease. Arch. Physiol. Biochem. 2008, 114, 127–149. [Google Scholar] [CrossRef]
  57. Oner-Iyidogan, Y.; Tanrikulu-Kucuk, S.; Seyithanoglu, M.; Kocak, H.; Dogru-Abbasoglu, S.; Aydin, A.F.; Beyhan-Ozdas, S.; Yapislar, H.; Kocak-Toker, N. Effect of curcumin on hepatic heme oxygenase 1 expression in high fat diet fed rats: Is there a triangular relationship? Can. J. Physiol. Pharmacol. 2014, 92, 805–812. [Google Scholar] [CrossRef]
  58. McNally, S.J.; Harrison, E.M.; Ross, J.A.; Garden, O.J.; Wigmore, S.J. Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury. Transplantation 2006, 81, 623–626. [Google Scholar] [CrossRef]
  59. Cunningham, R.P.; Moore, M.P.; Moore, A.N.; Healy, J.C.; Roberts, M.D.; Rector, R.S.; Martin, J.S. Curcumin supplementation mitigates NASH development and progression in female Wistar rats. Physiol. Rep. 2018, 6, e13789. [Google Scholar] [CrossRef] [Green Version]
  60. Liu, Y.; Cheng, F.; Luo, Y.; Zhan, Z.; Hu, P.; Ren, H.; Tang, H.; Peng, M. PEGylated Curcumin Derivative Attenuates Hepatic Steatosis via CREB/PPAR-gamma/CD36 Pathway. Biomed. Res. Int. 2017, 2017, 8234507. [Google Scholar] [CrossRef] [Green Version]
  61. Mohammadi, S.; Karimzadeh Bardei, L.; Hojati, V.; Ghorbani, A.G.; Nabiuni, M. Anti-Inflammatory Effects of Curcumin on Insulin Resistance Index, Levels of Interleukin-6, C-Reactive Protein, and Liver Histology in Polycystic Ovary Syndrome-Induced Rats. Cell J. 2017, 19, 425–433. [Google Scholar] [CrossRef] [PubMed]
  62. Yan, C.; Zhang, Y.; Zhang, X.; Aa, J.; Wang, G.; Xie, Y. Curcumin regulates endogenous and exogenous metabolism via Nrf2-FXR-LXR pathway in NAFLD mice. Biomed. Pharmacother. 2018, 105, 274–281. [Google Scholar] [CrossRef] [PubMed]
  63. Lee, D.E.; Lee, S.J.; Kim, S.J.; Lee, H.S.; Kwon, O.S. Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Nutrients 2019, 11, 2702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Jalali, M.; Mahmoodi, M.; Mosallanezhad, Z.; Jalali, R.; Imanieh, M.H.; Moosavian, S.P. The effects of curcumin supplementation on liver function, metabolic profile and body composition in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. Complement. Ther. Med. 2020, 48, 102283. [Google Scholar] [CrossRef]
  65. Baziar, N.; Parohan, M. The effects of curcumin supplementation on body mass index, body weight, and waist circumference in patients with nonalcoholic fatty liver disease: A systematic review and dose-response meta-analysis of randomized controlled trials. Phytother. Res. 2020, 34, 464–474. [Google Scholar] [CrossRef]
  66. Saadati, S.; Sadeghi, A.; Mansour, A.; Yari, Z.; Poustchi, H.; Hedayati, M.; Hatami, B.; Hekmatdoost, A. Curcumin and inflammation in non-alcoholic fatty liver disease: A randomized, placebo controlled clinical trial. BMC Gastroenterol. 2019, 19, 133. [Google Scholar] [CrossRef]
  67. Hariri, M.; Gholami, A.; Mirhafez, S.R.; Bidkhori, M.; Sahebkar, A. A pilot study of the effect of curcumin on epigenetic changes and DNA damage among patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, clinical trial. Complement. Ther. Med. 2020, 51, 102447. [Google Scholar] [CrossRef]
  68. Cerletti, C.; Colucci, M.; Storto, M.; Semeraro, F.; Ammollo, C.T.; Incampo, F.; Costanzo, S.; De Bartolomeo, G.; Portincasa, P.; Barone, M.; et al. Randomised trial of chronic supplementation with a nutraceutical mixture in subjects with non-alcoholic fatty liver disease. Br. J. Nutr. 2020, 123, 190–197. [Google Scholar] [CrossRef]
  69. Schubert, S.Y.; Lansky, E.P.; Neeman, I. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J. Ethnopharmacol. 1999, 66, 11–17. [Google Scholar] [CrossRef]
  70. Krueger, D.A. Composition of pomegranate juice. J. AOAC Int. 2012, 95, 163–168. [Google Scholar] [CrossRef]
  71. Sodhi, K.; Puri, N.; Favero, G.; Stevens, S.; Meadows, C.; Abraham, N.G.; Rezzani, R.; Ansinelli, H.; Lebovics, E.; Shapiro, J.I. Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet. PLoS ONE 2015, 10, e0128648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. González-Ortiz, M.; Martínez-Abundis, E.; Espinel-Bermúdez, M.C.; Pérez-Rubio, K.G. Effect of pomegranate juice on insulin secretion and sensitivity in patients with obesity. Ann. Nutr. Metab. 2011, 58, 220–223. [Google Scholar] [CrossRef] [PubMed]
  73. McFarlin, B.K.; Strohacker, K.A.; Kueht, M.L. Pomegranate seed oil consumption during a period of high-fat feeding reduces weight gain and reduces type 2 diabetes risk in CD-1 mice. Br. J. Nutr. 2009, 102, 54–59. [Google Scholar] [CrossRef] [PubMed]
  74. Vroegrijk, I.O.; van Diepen, J.A.; van den Berg, S.; Westbroek, I.; Keizer, H.; Gambelli, L.; Hontecillas, R.; Bassaganya-Riera, J.; Zondag, G.C.; Romijn, J.A.; et al. Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice. Food Chem. Toxicol. 2011, 49, 1426–1430. [Google Scholar] [CrossRef] [PubMed]
  75. Abidov, M.; Ramazanov, Z.; Seifulla, R.; Grachev, S. The effects of Xanthigen in the weight management of obese premenopausal women with non-alcoholic fatty liver disease and normal liver fat. Diabetes Obes. Metab. 2010, 12, 72–81. [Google Scholar] [CrossRef] [PubMed]
  76. Raffaele, M.; Licari, M.; Amin, S.; Alex, R.; Shen, H.H.; Singh, S.P.; Vanella, L.; Rezzani, R.; Bonomini, F.; Peterson, S.J.; et al. Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice. Int. J. Mol. Sci. 2020, 21, 5469. [Google Scholar] [CrossRef]
  77. Waldman, M.; Arad, M.; Abraham, N.G.; Hochhauser, E. The PGC-1alpha -HO-1 axis, a powerful antioxidative pathway with potential to attenuate diabetic cardiomyopathy. Antioxid. Redox Signal. 2020, 32, 1273–1290. [Google Scholar] [CrossRef]
  78. Meddeb, W.; Rezig, L.; Abderrabba, M.; Lizard, G.; Mejri, M. Tunisian Milk Thistle: An Investigation of the Chemical Composition and the Characterization of Its Cold-Pressed Seed Oils. Int. J. Mol. Sci. 2017, 18, 2582. [Google Scholar] [CrossRef] [Green Version]
  79. Pittala, V.; Vanella, L.; Salerno, L.; Romeo, G.; Marrazzo, A.; Di Giacomo, C.; Sorrenti, V. Effects of Polyphenolic Derivatives on Heme Oxygenase-System in Metabolic Dysfunctions. Curr. Med. Chem. 2018, 25, 1577–1595. [Google Scholar] [CrossRef]
  80. Ni, X.; Wang, H. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD). Am. J. Transl. Res. 2016, 8, 1073–1081. [Google Scholar]
  81. Clichici, S.; Olteanu, D.; Nagy, A.L.; Oros, A.; Filip, A.; Mircea, P.A. Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl(4)-treated rats. J. Med. Food 2015, 18, 290–298. [Google Scholar] [CrossRef] [PubMed]
  82. Pais, P.; D’Amato, M. In vivo efficacy study of milk thistle extract (ETHIS-094) in STAM model of nonalcoholic steatohepatitis. Drugs R&D 2014, 14, 291–299. [Google Scholar] [CrossRef] [Green Version]
  83. Suk, J.; Jasprova, J.; Biedermann, D.; Petraskova, L.; Valentova, K.; Kren, V.; Muchova, L.; Vitek, L. Isolated Silymarin Flavonoids Increase Systemic and Hepatic Bilirubin Concentrations and Lower Lipoperoxidation in Mice. Oxid. Med. Cell Longev. 2019, 2019, 6026902. [Google Scholar] [CrossRef] [PubMed]
  84. Hinds, T.D., Jr.; Hosick, P.A.; Chen, S.; Tukey, R.H.; Hankins, M.W.; Nestor-Kalinoski, A.; Stec, D.E. Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha. Am. J. Physiol. Endocrinol. Metab. 2017, 312, E244–E252. [Google Scholar] [CrossRef] [Green Version]
  85. Hinds, T.D., Jr.; Burns, K.A.; Hosick, P.A.; McBeth, L.; Nestor-Kalinoski, A.; Drummond, H.A.; AlAmodi, A.A.; Hankins, M.W.; Vanden Heuvel, J.P.; Stec, D.E. Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha. J. Biol. Chem. 2016, 291, 25179–25191. [Google Scholar] [CrossRef] [Green Version]
  86. Kwak, M.S.; Kim, D.; Chung, G.E.; Kang, S.J.; Park, M.J.; Kim, Y.J.; Yoon, J.H.; Lee, H.S. Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease. Clin. Mol. Hepatol. 2012, 18, 383–390. [Google Scholar] [CrossRef]
  87. Hjelkrem, M.; Morales, A.; Williams, C.D.; Harrison, S.A. Unconjugated hyperbilirubinemia is inversely associated with non-alcoholic steatohepatitis (NASH). Aliment. Pharmacol. Ther. 2012, 35, 1416–1423. [Google Scholar] [CrossRef]
  88. Puri, K.; Nobili, V.; Melville, K.; Corte, C.D.; Sartorelli, M.R.; Lopez, R.; Feldstein, A.E.; Alkhouri, N. Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children. J. Pediatr. Gastroenterol. Nutr. 2013, 57, 114–118. [Google Scholar] [CrossRef]
  89. Hinds, T.D., Jr.; Adeosun, S.O.; Alamodi, A.A.; Stec, D.E. Does bilirubin prevent hepatic steatosis through activation of the PPARalpha nuclear receptor? Med. Hypotheses 2016, 95, 54–57. [Google Scholar] [CrossRef] [Green Version]
  90. Shen, H.H.; Alex, R.; Bellner, L.; Raffaele, M.; Licari, M.; Vanella, L.; Stec, D.E.; Abraham, N.G. Milk thistle seed cold press oil attenuates markers of the metabolic syndrome in a mouse model of dietary-induced obesity. J. Food Biochem. 2020, e13522. [Google Scholar] [CrossRef]
  91. Mathieu, P.; Lemieux, I.; Despres, J.P. Obesity, inflammation, and cardiovascular risk. Clin. Pharmacol. Ther. 2010, 87, 407–416. [Google Scholar] [CrossRef] [PubMed]
  92. Bouasla, I.; Bouasla, A.; Boumendjel, A.; Messarah, M.; Abdennour, C.; Boulakoud, M.S.; El Feki, A. Nigella sativa oil reduces aluminium chloride-induced oxidative injury in liver and erythrocytes of rats. Biol. Trace Elem. Res. 2014, 162, 252–261. [Google Scholar] [CrossRef]
  93. Al-Ghamdi, M.S. Protective effect of Nigella sativa seeds against carbon tetrachloride-induced liver damage. Am. J. Chin. Med. 2003, 31, 721–728. [Google Scholar] [CrossRef] [PubMed]
  94. Erisgin, Z.; Atasever, M.; Cetinkaya, K.; Akarca Dizakar, S.O.; Omeroglu, S.; Sahin, H. Protective effects of Nigella sativa oil against carboplatin-induced liver damage in rats. Biomed. Pharmacother. 2019, 110, 742–747. [Google Scholar] [CrossRef] [PubMed]
  95. Mao, M.; Li, J.; Bi, A.; Jia, H.; Li, Q.; Liu, Y.; Jiang, X.; Huang, D.; Xia, S. Thymoquinone ameliorates the PM2.5-induced lung injury in rats. Exp. Lung Res. 2020, 46, 297–307. [Google Scholar] [CrossRef] [PubMed]
  96. Jaarin, K.; Foong, W.D.; Yeoh, M.H.; Kamarul, Z.Y.; Qodriyah, H.M.; Azman, A.; Zuhair, J.S.; Juliana, A.H.; Kamisah, Y. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats. Clinics (Sao Paulo) 2015, 70, 751–757. [Google Scholar] [CrossRef]
  97. Licari, M.; Raffaele, M.; Rosman, Z.F.; Schragenheim, J.; Bellner, L.; Vanella, L.; Rezzani, R.; Rodella, L.; Bonomini, F.; Hochhauser, E.; et al. Abraham NG. Beneficial Effects of Thymoquinone on Metabolic Function and Fatty Liver in a Murine Model of Obesity. J. Nutr. Food Sci. 2019, 9. [Google Scholar] [CrossRef]
  98. Shen, H.H.; Peterson, S.J.; Bellner, L.; Choudhary, A.; Levy, L.; Gancz, L.; Sasson, A.; Trainer, J.; Rezzani, R.; Resnick, A.; et al. Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice. Antioxidants 2020, 9, 489. [Google Scholar] [CrossRef]
  99. Kundu, J.; Kim, D.H.; Kundu, J.K.; Chun, K.S. Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKalpha as upstream targets. Food Chem. Toxicol. 2014, 65, 18–26. [Google Scholar] [CrossRef]
  100. Rashidmayvan, M.; Mohammadshahi, M.; Seyedian, S.S.; Haghighizadeh, M.H. The effect of Nigella sativa oil on serum levels of inflammatory markers, liver enzymes, lipid profile, insulin and fasting blood sugar in patients with non-alcoholic fatty liver. J. Diabetes Metab. Disord. 2019, 18, 453–459. [Google Scholar] [CrossRef]
  101. Zhuang, H.; Kim, Y.S.; Koehler, R.C.; Dore, S. Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann. N. Y. Acad. Sci. 2003, 993, 276–286. [Google Scholar] [CrossRef] [PubMed]
  102. Sakata, Y.; Zhuang, H.; Kwansa, H.; Koehler, R.C.; Dore, S. Resveratrol protects against experimental stroke: Putative neuroprotective role of heme oxygenase 1. Exp. Neurol. 2010, 224, 325–329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Thirunavukkarasu, M.; Penumathsa, S.V.; Koneru, S.; Juhasz, B.; Zhan, L.; Otani, H.; Bagchi, D.; Das, D.K.; Maulik, N. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic. Biol. Med. 2007, 43, 720–729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Das, S.; Fraga, C.G.; Das, D.K. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic. Res. 2006, 40, 1066–1075. [Google Scholar] [CrossRef]
  105. Cheng, A.S.; Cheng, Y.H.; Chiou, C.H.; Chang, T.L. Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. J. Agric. Food Chem. 2012, 60, 9180–9187. [Google Scholar] [CrossRef] [PubMed]
  106. Chen, C.Y.; Jang, J.H.; Li, M.H.; Surh, Y.J. Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem. Biophys. Res. Commun. 2005, 331, 993–1000. [Google Scholar] [CrossRef] [PubMed]
  107. Hosseini, H.; Teimouri, M.; Shabani, M.; Koushki, M.; Babaei Khorzoughi, R.; Namvarjah, F.; Izadi, P.; Meshkani, R. Resveratrol alleviates non-alcoholic fatty liver disease through epigenetic modification of the Nrf2 signaling pathway. Int. J. Biochem. Cell Biol. 2020, 119, 105667. [Google Scholar] [CrossRef]
  108. Gomez-Zorita, S.; Fernandez-Quintela, A.; Macarulla, M.T.; Aguirre, L.; Hijona, E.; Bujanda, L.; Milagro, F.; Martinez, J.A.; Portillo, M.P. Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. Br. J. Nutr. 2012, 107, 202–210. [Google Scholar] [CrossRef] [Green Version]
  109. Bujanda, L.; Hijona, E.; Larzabal, M.; Beraza, M.; Aldazabal, P.; Garcia-Urkia, N.; Sarasqueta, C.; Cosme, A.; Irastorza, B.; Gonzalez, A.; et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol. 2008, 8, 40. [Google Scholar] [CrossRef] [Green Version]
  110. Wang, G.L.; Fu, Y.C.; Xu, W.C.; Feng, Y.Q.; Fang, S.R.; Zhou, X.H. Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem. Biophys. Res. Commun. 2009, 380, 644–649. [Google Scholar] [CrossRef]
  111. Izdebska, M.; Herbet, M.; Gawronska-Grzywacz, M.; Piatkowska-Chmiel, I.; Korga, A.; Sysa, M.; Iwan, M.; Natorska-Chomicka, D.; Poleszak, E.; Wrobel, A.; et al. Resveratrol Limits Lipogenesis and Enhance Mitochondrial Activity in HepG2 Cells. J. Pharm. Pharm. Sci. 2018, 21, 504–515. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Teng, W.; Zhao, L.; Yang, S.; Zhang, C.; Liu, M.; Luo, J.; Jin, J.; Zhang, M.; Bao, C.; Li, D.; et al. The hepatic-targeted, resveratrol loaded nanoparticles for relief of high fat diet-induced nonalcoholic fatty liver disease. J. Control. Release 2019, 307, 139–149. [Google Scholar] [CrossRef] [PubMed]
  113. Wu, B.; Xiao, Z.; Zhang, W.; Chen, H.; Liu, H.; Pan, J.; Cai, X.; Liang, G.; Zhou, B.; Shan, X.; et al. A novel resveratrol-curcumin hybrid, a19, attenuates high fat diet-induced nonalcoholic fatty liver disease. Biomed. Pharmacother. 2019, 110, 951–960. [Google Scholar] [CrossRef] [PubMed]
  114. Hajighasem, A.; Farzanegi, P.; Mazaheri, Z. Effects of combined therapy with resveratrol, continuous and interval exercises on apoptosis, oxidative stress, and inflammatory biomarkers in the liver of old rats with non-alcoholic fatty liver disease. Arch. Physiol. Biochem. 2019, 125, 142–149. [Google Scholar] [CrossRef]
  115. Heeboll, S.; Kreuzfeldt, M.; Hamilton-Dutoit, S.; Kjaer Poulsen, M.; Stodkilde-Jorgensen, H.; Moller, H.J.; Jessen, N.; Thorsen, K.; Kristina Hellberg, Y.; Bonlokke Pedersen, S.; et al. Placebo-controlled, randomised clinical trial: High-dose resveratrol treatment for non-alcoholic fatty liver disease. Scand. J. Gastroenterol. 2016, 51, 456–464. [Google Scholar] [CrossRef]
  116. Chachay, V.S.; Macdonald, G.A.; Martin, J.H.; Whitehead, J.P.; O’Moore-Sullivan, T.M.; Lee, P.; Franklin, M.; Klein, K.; Taylor, P.J.; Ferguson, M.; et al. Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2014, 12, 2092–2103.e1–6. [Google Scholar] [CrossRef] [Green Version]
  117. Kantartzis, K.; Fritsche, L.; Bombrich, M.; Machann, J.; Schick, F.; Staiger, H.; Kunz, I.; Schoop, R.; Lehn-Stefan, A.; Heni, M.; et al. Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: A randomized, double-blind, placebo-controlled clinical trial. Diabetes Obes. Metab. 2018, 20, 1793–1797. [Google Scholar] [CrossRef]
  118. Farzin, L.; Asghari, S.; Rafraf, M.; Asghari-Jafarabadi, M.; Shirmohammadi, M. No beneficial effects of resveratrol supplementation on atherogenic risk factors in patients with nonalcoholic fatty liver disease. Int. J. Vitam. Nutr. Res. 2020, 90, 279–289. [Google Scholar] [CrossRef]
  119. Elgebaly, A.; Radwan, I.A.; AboElnas, M.M.; Ibrahim, H.H.; Eltoomy, M.F.; Atta, A.A.; Mesalam, H.A.; Sayed, A.A.; Othman, A.A. Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis. J. Gastrointestin. Liver Dis. 2017, 26, 59–67. [Google Scholar] [CrossRef]
  120. Jakubczyk, K.; Skonieczna-Zydecka, K.; Kaldunska, J.; Stachowska, E.; Gutowska, I.; Janda, K. Effects of Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease-A Meta-Analysis. Nutrients 2020, 12, 2435. [Google Scholar] [CrossRef]
  121. Weis, N.; Weigert, A.; von Knethen, A.; Brune, B. Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants. Mol. Biol. Cell 2009, 20, 1280–1288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Zhang, M.; Nakamura, K.; Kageyama, S.; Lawal, A.O.; Gong, K.W.; Bhetraratana, M.; Fujii, T.; Sulaiman, D.; Hirao, H.; Bolisetty, S.; et al. Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury. JCI Insight 2018, 3. [Google Scholar] [CrossRef] [PubMed]
Ijms 21 09493 g001 550
Figure 1. Schematic diagram on the potential role of natural product HO-1 inducers in NAFLD. In NAFLD, HO-1 levels are suppressed by several mechanisms, including increased BACH1 activity. This increases reactive oxygen species (ROS) levels as well as macrophage M1 polarization as opposed to M2, both of which contribute to increasing triglyceride accumulation and reductions in glycogen content. Natural product induction of HO-1 decreases M1 macrophage levels and their resultant inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), cluster of differentiation 68 (ED1), monocyte chemoattractant protein-1 (MCP-1), and at the same time increases M2 macrophage levels and their resultant anti-inflammatory cytokines, ED2, interleukin-10 (IL-10), and mannose receptor (CD-206). HO-1 also increases the activity of peroxisome proliferator-activated receptor-α (PPARα) to decrease hepatic triglyceride levels and increase hepatic glycogen content. ↑ indicate “increase” and ↓ indicate “decrease” respectively. The white circles represent fat droplets and the purple circles represent glycogen deposits in the liver.
Figure 1. Schematic diagram on the potential role of natural product HO-1 inducers in NAFLD. In NAFLD, HO-1 levels are suppressed by several mechanisms, including increased BACH1 activity. This increases reactive oxygen species (ROS) levels as well as macrophage M1 polarization as opposed to M2, both of which contribute to increasing triglyceride accumulation and reductions in glycogen content. Natural product induction of HO-1 decreases M1 macrophage levels and their resultant inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), cluster of differentiation 68 (ED1), monocyte chemoattractant protein-1 (MCP-1), and at the same time increases M2 macrophage levels and their resultant anti-inflammatory cytokines, ED2, interleukin-10 (IL-10), and mannose receptor (CD-206). HO-1 also increases the activity of peroxisome proliferator-activated receptor-α (PPARα) to decrease hepatic triglyceride levels and increase hepatic glycogen content. ↑ indicate “increase” and ↓ indicate “decrease” respectively. The white circles represent fat droplets and the purple circles represent glycogen deposits in the liver.
Ijms 21 09493 g001
Table
Table 1. Summary of preclinical and clinical studies of natural product HO-1 inducers on nonalcoholic fatty liver disease (NAFLD). HFD, high fat diet; Gal-OSL/Res- D- (+) galactose- oxidized starch-lysozyme/resveratrol.
Table 1. Summary of preclinical and clinical studies of natural product HO-1 inducers on nonalcoholic fatty liver disease (NAFLD). HFD, high fat diet; Gal-OSL/Res- D- (+) galactose- oxidized starch-lysozyme/resveratrol.
ProductModel/AdministrationEffectReference
CurcuminWistar Rats/~100 mg/kg body weight/dayProtective against NAFD & NASH[59]
C57BL/6J mice HFD/Pegylated 50–100 mg/kgProtective against NAFD & NASH[60]
Meta-analysis in NAFLD Patients/> /< 500 mg/dayFavorable effect on metabolic markers[64]
Meta-analysis in NAFLD Patients/70 to 3000 mg/day Positive effect on visceral fat and abdominal obesity [65]
50 NAFLD Patients/1500 mg/day, 12 weeksNo effect on steatosis, slight effect on fibrosis[67]
113 NAFLD Patients/35 mg/day, 3 monthsNo effect on steatosis or metabolic parameters[68]
Pomegranate Seed OilCd-1 mice HFD/61.79 mg/day, 14 weeksLowered body weight and improved insulin sensitivity[69]
C57BL/6J mice HFD/1% wt:wt in diet, 12 weeks Ameliorated high-fat diet induced obesity and insulin resistance [70]
NAFLD and control patients/200–300 mg/day, 16 weeksLowered hepatic steatosis and improved liver function[71]
C57BL/6J mice HFD/40 mL/kg food, 8 weeksProtective against hepatic steatosis and fibrosis[72]
Milk Thistle Seed OilC57BL/6J mice HFD/500–1000 mg/kg, 4 weeksProtective against NAFD & NASH[73]
C57BL/6J mice HFD/2%/kg/day, 8 weeksAttenuation of hepatic steatosis, inflammation, and insulin resistance[74]
Cold Pressed Nigella Sativa OilC57BL/6J mice HFD/3%, 8 weeksAttenuation of hepatic steatosis, induction of HO-1 and improved mitochondrial function[75]
C57BL/6J mice HFD/3%, 8 weeksAttenuation of hepatic steatosis, induction of HO-1 and improved mitochondrial function[76]
44 NAFLD Patients/1 g/day oral, 8 weeksImproved lipid profile, markers of inflammation, and liver enzymes[77]
ResveratrolZucker Fatty Rats/15 mg/kg body weight/dayReduced hepatic steatosis and oxidative stress[78]
Wistar Rats (a high carbohydrate-fat free modified diet)/10 mg/day oralReduced hepatic steatosis, oxidative stress, and inflammation[79]
HepG2 Cells/0.2–40 μMReduced lipid accumulation, increased Sirt1-Fox0, improved mitochondrial function[80,81]
C57BL/6J mice HFD/Gal-OSL/Res 200 mg/kg i.v. every other dayProtective against NAFLD[82]
28 NAFLD patients/1500 mg/day, 8 weeksNo effect on NAFLD[83]
20 Male NAFLD patientsNo effect on NAFLD[84]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Stec, D.E.; Hinds, T.D., Jr. Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2020, 21, 9493. https://doi.org/10.3390/ijms21249493

AMA Style

Stec DE, Hinds TD Jr. Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences. 2020; 21(24):9493. https://doi.org/10.3390/ijms21249493

Chicago/Turabian Style

Stec, David E., and Terry D. Hinds, Jr. 2020. "Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease" International Journal of Molecular Sciences 21, no. 24: 9493. https://doi.org/10.3390/ijms21249493

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