Molecular insights into the role of mitochondria in non-alcoholic fatty liver disease

Liu, Jin; Park, Jeong-Su; Roh, Yoon Seok

doi:10.1007/s12272-019-01178-1

Cited by 94 publications

(75 citation statements)

References 101 publications

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“…The pathogenesis of NAFLD arises from aberrant lipid metabolism in the liver, which is characterized by increased lipogenesis and elevated hepatocytes free fatty acid (FFA) uptake caused by insulin resistance. The lipotoxicity triggers a series of second hits including mitochondrial dysfunction, excessive oxidative stress, ER stress, inflammation, and profibrogenic response, predisposing the liver to high-risk conditions [128]. Considering the key role of the mitochondria in fatty acid metabolism and energy generation, impaired mitochondrial function is thought to be a hallmark of NAFLD [129].…”

Section: Mitophagy In Nafldmentioning

confidence: 99%

Role and Mechanisms of Mitophagy in Liver Diseases

McKeen

Zhang

et al. 2020

Cells

165

122

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The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.

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Section: Mitophagy In Nafldmentioning

confidence: 99%

Role and Mechanisms of Mitophagy in Liver Diseases

McKeen

Zhang

et al. 2020

Cells

165

122

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“…[19] Because mitochondrial dysfunction leads to increased production of ROS and inflammation and decreased fatty acid oxidation, the role of mitochondria appears to be central to the mechanism contributing to the pathogenesis of NAFLD and NASH. [20] Therefore, because Nrf2 is critical for mitochondrial homeostasis, lipid metabolism, and overall hepatoprotection, [21] the effects of omaveloxolone and a closely related analog, TX63682, were investigated in the STAM mouse model of NASH. [22] Diabetes and obesity are key features of the STAM model, which has been described to recapitulate the known progression of the human disease.…”

mentioning

confidence: 99%

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

Reisman

Ferguson

Lee

et al. 2020

J Biochem & Molecular Tox

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Omaveloxolone is a potent activator of Nrf2, a master transcriptional regulator of a multitude of cytoprotective functions, including antioxidative, anti‐inflammatory, and mitochondrial bioenergetic effects. Some of the most potent known effects of Nrf2 involve hepatoprotective functions. The purpose of this study was to evaluate the effects of omaveloxolone and TX63682, a closely related structural analog with similar oral bioavailability, in the STAM mouse model of nonalcoholic steatohepatitis (NASH). C57Bl/6 mice received a single subcutaneous injection of streptozotocin two days after birth and were fed a high‐fat diet from 4 to 9 weeks of age. Omaveloxolone and TX63682 were orally administered at doses of 1, 3, and 10 mg/kg/d from 6 to 9 weeks of age. Consistent with the beneficial effects of Nrf2 on hepatoprotection and improved lipid handling, both omaveloxolone and TX63682 decreased hepatic fat deposition, hepatocellular ballooning, inflammatory cell infiltration, and collagen deposition. Omaveloxolone and TX63682 also improved blood glucose control, as evidenced by reductions in nonfasting blood glucose and glycated hemoglobin A1C concentrations. Reductions in liver and serum triglycerides with omaveloxolone and TX63682 treatment were also observed. Both omaveloxolone and TX63682 decreased leptin and increased adiponectin in serum, which is consistent with the anti‐inflammatory and antifibrotic effects observed in the liver. These results were associated with significant induction of Nrf2 target gene expression in the liver, including NAD(P)H:quinone oxidoreductase 1, sulfiredoxin 1, and ferritin heavy chain 1. Overall, these data suggest that omaveloxolone and related Nrf2 activators may be useful for the treatment of NASH.

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“…In an alcoholic liver disease model, hepatocytes generate exosomal mtdsRNA to mediate TLR3 activation and subsequent IL-1β expression in KC [106]. Mitochondrial N-formyl peptides were released from hepatocyte trigger formyl peptide receptor 1 on KC, subsequently stimulating NF-κB activity [5]. Our recent work demonstrated that WT mice fed with HFD developed hepatic inflammation and fibrosis and had increased mtDNA and TFAM in the liver tissue, while those same phenomena in miR-29a transgene mice fed with HFD are greatly reduced [44], indicating that miR-29a may exert an anti-inflammatory effect on the pathogenesis of NAFLD by restricting mtDAMPs.…”

Section: Role Of Mir-29a In Oxidative Stress and Inflammationmentioning

confidence: 99%

“…Inflammatory mediators secreted by activated KC trigger activation of HSC. HSC activation consequently plays a central role for liver fibrogenesis, because these cells transdifferentiate into myofibroblasts and represent the major extracellular matrix producing cells [5,153,154]. Free cholesterol accumulation caused-lipotoxicity sensitizes HSCs to TGFβ-induced activation through TLR4 signaling in NASH mouse model [155].…”

Section: The Role Of Mir-29a In Fibrogenesismentioning

confidence: 99%

“…NAFLD is a hepatic manifestation of the metabolic syndrome [2] and is closely associated with cardio-and neurological complications, including cardiovascular disease, hypertension, cognitive dysfunction, and ischemic stroke [3,4]. NAFLD may result from "multiple and parallel hits" like lipotoxicity caused by the excessively elevated uptake of fatty acid (FA) into hepatocytes, subsequently elevated oxidative stress, and the activation of proinflammatory mediators of Kupffer cells (KC), as well as fibrogenic pathways of activated hepatic stellar cells (HSC), leading to non-alcoholic steatohepatitis (NASH) and non-alcoholic steatofibrosis (NASF) [5]. Considered a key predisposing factor for cirrhosis, NASH is implicated as a risk factor for non-viral hepatitis-related hepatocellular carcinoma (HCC) [6].…”

Section: Introductionmentioning

confidence: 99%

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

Lin

Yang

Wang

et al. 2020

Cells

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

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Molecular insights into the role of mitochondria in non-alcoholic fatty liver disease

Cited by 94 publications

References 101 publications

Role and Mechanisms of Mitophagy in Liver Diseases

Role and Mechanisms of Mitophagy in Liver Diseases

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

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

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