WITHDRAWN: Loss of hepatic HIF-1α accelerates lipid accumulation by inhibiting peroxisomal fatty acid oxidation in nonalcoholic fatty liver disease

2015 ◽  
Author(s):  
Takatomo Arai ◽  
Yuki Kato ◽  
Kenji Ishimoto ◽  
Mai Kanai ◽  
Satoko Shinjo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Nonalcoholic Fatty Liver ◽  
Peroxisomal Fatty Acid Oxidation ◽  
Peroxisomal Fatty Acid

scholarly journals Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

2016 ◽  
Vol 36 (20) ◽  
pp. 2553-2567 ◽  
Author(s):  
Liang Guo ◽  
Shui-Rong Zhou ◽  
Xiang-Bo Wei ◽  
Yuan Liu ◽  
Xin-Xia Chang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Acid Oxidation ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Α Subunit ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Trifunctional Protein

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPα. Replacement of MTPα-3K with either MTPα-3KR or MTPα-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPα-3K mutant expression in mouse livers, and MTPα-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPα and MTPα-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPα regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

scholarly journals Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

2022 ◽  
Vol 12 ◽  
Author(s):  
Fei Zhou ◽  
Mingning Ding ◽  
Yiqing Gu ◽  
Guifang Fan ◽  
Chuanyang Liu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD), manifested as the aberrant accumulation of lipids in hepatocytes and inflammation, has become an important cause of advanced liver diseases and hepatic malignancies worldwide. However, no effective therapy has been approved yet. Aurantio-obtusin (AO) is a main bioactive compound isolated from Cassia semen that has been identified with multiple pharmacological activities, including improving adiposity and insulin resistance. However, the ameliorating effects of AO on diet-induced NAFLD and underlying mechanisms remained poorly elucidated. Our results demonstrated that AO significantly alleviated high-fat diet and glucose-fructose water (HFSW)-induced hepatic steatosis in mice and oleic acid and palmitic acid (OAPA)-induced lipid accumulation in hepatocytes. Remarkably, AO was found to distinctly promote autophagy flux and influence the degradation of lipid droplets by inducing AMPK phosphorylation. Additionally, the induction of AMPK triggered TFEB activation and promoted fatty acid oxidation (FAO) by activating PPARα and ACOX1 and decreasing the expression of genes involved in lipid biosynthesis. Meanwhile, the lipid-lowing effect of AO was significantly prevented by the pretreatment with inhibitors of autophagy, PPARα or ACOX1, respectively. Collectively, our study suggests that AO ameliorates hepatic steatosis via AMPK/autophagy- and AMPK/TFEB-mediated suppression of lipid accumulation, which opens new opportunities for pharmacological treatment of NAFLD and associated complications.

scholarly journals Hypoxia exacerbates nonalcoholic fatty liver disease via the HIF-2α/PPARα pathway

2019 ◽  
Vol 317 (4) ◽  
pp. E710-E722 ◽  
Author(s):  
Jiandi Chen ◽  
Jianxu Chen ◽  
Huirong Fu ◽  
Yun Li ◽  
Lingling Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Intermittent Hypoxia ◽  
Peroxisome Proliferator ◽  
Nonalcoholic Fatty Liver

This study aimed to investigate whether hypoxia can affect nonalcoholic fatty liver disease (NAFLD) progression and the associated mechanisms, specifically regarding the hypoxia-inducible factor (HIF)-2α/peroxisome proliferator-activated receptor (PPAR)α pathway in vitro and in vivo. Recent studies have reported that, compared with HIF-1α, HIF-2α has different effects on lipid metabolism. We propose hypoxia may exacerbate NAFLD by the HIF-2α upregulation-induced suppression of PPARα in the liver. To verify this hypothesis, a steatotic human hepatocyte (L02) cell line treated with free fatty acids and a mouse model of NAFLD fed a high-fat diet were used. Steatotic hepatocytes were treated with hypoxia, HIF-2α siRNA, PPARα agonists, and inhibitors, respectively. Meanwhile, the NAFLD mice were exposed to intermittent hypoxia or intermittent hypoxia with PPARα agonists. The relative gene expression levels of HIF-1α, HIF-2α, mitochondrial function, fatty acid β-oxidation and lipogenesis were examined. Evidence of lipid accumulation was observed, which demonstrated that, compared with normal hepatocytes, steatotic hepatocytes exhibited higher sensitivity to hypoxia. This phenomenon was closely associated with HIF-2α. Moreover, lipid accumulation in hepatocytes was ameliorated by HIF-2α silencing or a PPARα agonist, despite the hypoxia treatment. HIF-2α overexpression under hypoxic conditions suppressed PPARα, leading to PGC-1α, NRF-1, ESRRα downregulation, and mitochondrial impairment. Additionally, β-oxidation genes such as CPT1α, CPT2α, ACOX1, and ACOX2 were downregulated and lipogenesis genes including LXRα, FAS, and SCD1 were upregulated by hypoxia. Therefore, we concluded that HIF-2α overexpression induced by hypoxia aggravated NAFLD progression by suppressing fatty acid β-oxidation and inducing lipogenesis in the liver via PPARα.

scholarly journals Diospyros kaki and Citrus unshiu Mixture Improves Disorders of Lipid Metabolism in Nonalcoholic Fatty Liver Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Mi-Rae Shin ◽  
Sung Ho Shin ◽  
Seong-Soo Roh
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Diospyros Kaki ◽  
Citrus Unshiu ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) has been a major cause of a chronic liver disease over recent decades and increasing worldwide in parallel with the remarkable growth of obesity. In the present study, we investigate the ameliorative effects of PCM, a combination of Diospyros kaki fruit and Citrus unshiu peel mixture, on high-fat diet- (HFD-) induced NAFLD and clarify the potential mechanisms. PCM in HFD-fed mice was orally administered at a dose of 50 or 100 mg/kg subsequently for 2 months. Thereafter, lipid metabolism parameters and fat synthesis-related genes in the mouse liver were evaluated. Subsequently, body weight changes, liver weight, serum liver function and lipid profiles, and liver pathology were examined, and the relative levels of fatty acid synthesis and β-oxidation gene expression were evaluated by western blot. Serum AST, ALT, and TG levels in the HFD control mice were significantly higher than those of normal mice. Compared with HFD control mice, PCM supplementation increased phosphorylation of AMP-activated protein kinase (AMPK). Peroxisome proliferator-activated receptor (PPAR) α was significantly increased by PCM administration. Continuously, the activation of PPARα significantly elevated carnitine palmitoyltransferase 1 (CPT-1), a key enzyme in fatty acid β-oxidation, and mitochondrial uncoupling protein 2 (UCP-2), thermogenic regulatory genes, in PCM-treated mice compared with those of HFD control mice. Moreover, PCM inhibits lipogenesis and cholesterol synthesis via suppression of sterol regulatory element binding protein-1 (SREBP-1) and SREBP-2 and its target genes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Taken together, these effects were mediated through activation of AMPK. In the conclusion, PCM improved liver damage in HFD-fed mice and attenuated NAFLD by the activation of PPARα and the inhibition of SREBPs expression via AMPK-dependent pathways.

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