scholarly journals Fat Mass and Obesity–Associated Protein Promotes Liver Steatosis By Targeting PPARα

2022 ◽  
Author(s):  
Xiaohui Wei ◽  
Jielei Zhang ◽  
Min Tang ◽  
Xuejiao Wang ◽  
Nengguang Fan ◽  
...  
Keyword(s):  
Liver Disease ◽  
Hepatic Steatosis ◽  
Fat Mass ◽  
Lipid Accumulation ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Peroxisome Proliferator ◽  
Cellular Models ◽  
Triglyceride Accumulation

Abstract Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The fat mass and obesity–associated protein (FTO) has been shown to be involved in obesity; however, its role in NAFLD and the underlying molecular mechanisms remain largely unknown. Methods: FTO expression was first examined in the livers of patients with NAFLD and animal and cellular models of NAFLD using quantitative real-time polymerase chain reaction and western blotting. Next, its role in lipid accumulation in hepatocytes was assessed both in vitro and in vivo via gene overexpression and knockdown studies. Results: FTO expression was increased in the livers of mice and humans with hepatic steatosis, probably due to its decreased ubiquitination. FTO overexpression in HepG2 cells induced triglyceride accumulation, whereas FTO knockdown exerted an opposing effect. Consistent with the findings of in vitro studies, adeno-associated viruses 8 (AAV8)-mediated FTO overexpression in the liver promoted hepatic steatosis in C57BL/6J mice. Mechanistically, FTO inhibited the mRNA expression of peroxisome proliferator-activated receptor α (PPARα) in hepatocytes. Activation of PPARα by the PPARα agonist GW7647 reversed lipid accumulation in hepatocytes induced by FTO overexpression.Conclusions: Overall, FTO expression is increased in NAFLD, and it promotes hepatic steatosis by targeting PPARα.

scholarly journals Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Ting Li ◽  
Ting Fang ◽  
Linxin Xu ◽  
Xiangyang Liu ◽  
Xiaoyu Li ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Liver Steatosis ◽  
Fatty Degeneration ◽  
Hepatic Lipid Accumulation ◽  
Compound C ◽  
Hepatocyte Steatosis ◽  
Autophagy Pathway

Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood.Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels.Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment.Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

scholarly journals CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression

2020 ◽  
Vol 6 (48) ◽  
pp. eabc5022
Author(s):  
Z. Yang ◽  
P. Li ◽  
Q. Shang ◽  
Y. Wang ◽  
J. He ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Critical Role ◽  
Liver Steatosis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Triglyceride Accumulation

Obesity drives the development of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis. Several bone morphogenetic proteins (BMPs) except BMP9 were reported related to metabolic syndrome. This study demonstrates that liver cytokine BMP9 is decreased in the liver and serum of NAFLD model mice and patients. BMP9 knockdown induces lipid accumulation in Hepa 1-6 cells. BMP9–knockout mice exhibit hepatosteatosis due to down-regulated peroxisome proliferator–activated receptor α (PPARα) expression and reduced fatty acid oxidation. In vitro, recombinant BMP9 treatment attenuates triglyceride accumulation by enhancing PPARα promoter activity via the activation of p-smad. PPARα-specific antagonist GW6471 abolishes the effect of BMP9 knockdown. Furthermore, adeno-associated virus–mediated BMP9 overexpression in mouse liver markedly relieves liver steatosis and obesity-related metabolic syndrome. These findings indicate that BMP9 plays a critical role in regulating hepatic lipid metabolism in a PPARα-dependent manner and may provide a previously unknown insight into NAFLD therapeutic approaches.

scholarly journals circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Xing-Ya Guo ◽  
Jian-Neng Chen ◽  
Fang Sun ◽  
Yu-Qin Wang ◽  
Qin Pan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Hepatic Steatosis ◽  
Transcriptional Activation ◽  
Regulatory System ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triglyceride Accumulation

Hepatic steatosis reflects the miRNA-related pathological disorder with triglyceride accumulation and lipid peroxidation, which leads to nonalcoholic steatohepatitis, liver fibrosis/cirrhosis, and even hepatocellular carcinoma. Circular RNA (circRNA)/miRNA interaction reveals a novel layer of epigenetic regulation, yet the miRNA-targeting circRNA remains uncertain in hepatic steatosis. Here, we uncover circRNA_0046367 to be endogenous modulator of miR-34a that underlies hepatic steatosis. In contrast to its expression loss during the hepatocellular steatosis in vivo and in vitro, circRNA_0046367 normalization abolished miR-34a’s inhibitory effect on peroxisome proliferator-activated receptorα(PPARα) via blocking the miRNA/mRNA interaction with miRNA response elements (MREs). PPARαrestoration led to the transcriptional activation of genes associated with lipid metabolism, including carnitine palmitoyltransferase 2 (CPT2) and acyl-CoA binding domain containing 3 (ACBD3), and then resulted in the steatosis resolution. Hepatotoxicity of steatosis-related lipid peroxidation, being characterized by mitochondrial dysfunction, growth arrest, and apoptosis, is resultantly prevented after the circRNA_0046367 administration. These findings indicate a circRNA_0046367/miR-34a/PPARαregulatory system underlying hepatic steatosis. Normalized expression of circRNA_0046367 may ameliorate the lipoxidative stress on the basis of steatosis attenuation. circRNA_0046367, therefore, is suggested to be potential approach to the therapy of lipid peroxidative damage.

scholarly journals Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach

2021 ◽  
Author(s):  
Jimmy Alarcan ◽  
Georges de Sousa ◽  
Efrosini S. Katsanou ◽  
Anastasia Spyropoulou ◽  
Petros Batakis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Receptor Activation ◽  
Adverse Outcome Pathway ◽  
Vitro Assay ◽  
Mixture Effects ◽  
Triglyceride Accumulation

AbstractWithin the EuroMix project, we have previously developed an adverse outcome pathway (AOP)-based in vitro assay toolbox to investigate the combined effects of liver steatosis-inducing compounds in human HepaRG hepatocarcinoma cells. In this study, we applied the toolbox to further investigate mixture effects of combinations, featuring either similarly acting or dissimilarly acting substances. The valproic acid structural analogs 2-propylheptanoic acid (PHP) and 2-propylhexanoic acid (PHX) were chosen for establishing mixtures of similarly acting substances, while a combination with the pesticidal active substance clothianidin (CTD) was chosen for establishing mixtures of dissimilarly acting compounds. We first determined relative potency factors (RPFs) for each compound based on triglyceride accumulation results. Thereafter, equipotent mixtures were tested for nuclear receptor activation in transfected HepG2 cells, while gene expression and triglyceride accumulation were investigated in HepaRG cells, following the proposed AOP for liver steatosis. Dose addition was observed for all combinations and endpoints tested, indicating the validity of the additivity assumption also in the case of the tested mixtures of dissimilarly acting substances. Gene expression results indicate that the existing steatosis AOP can still be refined with respect to the early key event (KE) of gene expression, in order to reflect the diversity of molecular mechanisms underlying the adverse outcome.

scholarly journals Sulforaphane Attenuates Nonalcoholic Fatty Liver Disease by Inhibiting Hepatic Steatosis and Apoptosis

Nutrients ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 76
Author(s):  
Jinwang Li ◽  
Siyu Xie ◽  
Wendi Teng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Lipid Deposition ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipotoxicity and ectopic lipid deposition within hepatocytes. Sulforaphane (SFA), an active compound used for inhibiting tumors, was found to have the potency to improve lipid metabolism. However, its molecular mechanisms on ameliorating NAFLD are still incompletely understood. This research evaluated if SFA could inhibit hepatic steatosis and apoptosis. The effects of SFA on cell viability, lipid accumulation, triglyceride (TG) contents, apoptosis, ceramide contents, and reactive oxygen species (ROS) levels were analyzed in palmitic acid (PA)-treated HepG2 cells and high-fat diet (HFD)-fed mice. The related molecular mechanisms were further explored in hepatocytes. The results showed SFA alleviated lipid accumulation and regulated AMPK/SREBP1c/FAS signaling pathway in PA-stressed HepG2 cells. In addition, SFA alleviated PA-mediated apoptosis, downregulated the expressions of cleaved caspase 3, as well as reduced ceramide contents and ROS levels. Moreover, SFA treatment reduced HFD-induced body weight gain, alleviated insulin resistance, decreased serum TG, total cholesterol (TC), and alanine aminotransferase (ALT) levels, and prevented lipid deposition and apoptosis in the liver. This study showed SFA suppressed lipid deposition and apoptosis both in vitro and in vivo, indicating that SFA may be a potential candidate for preventing and treating NAFLD.

scholarly journals Gallic Acid Inhibits Lipid Accumulation via AMPK Pathway and Suppresses Apoptosis and Macrophage-Mediated Inflammation in Hepatocytes

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1479
Author(s):  
Miori Tanaka ◽  
Akari Sato ◽  
Yoshimi Kishimoto ◽  
Hideaki Mabashi-Asazuma ◽  
Kazuo Kondo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Gallic Acid ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Molecular Mechanisms ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Apoptosis And Inflammation ◽  
Amp Activated Protein Kinase

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, sometimes ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Various hits including excessive hepatic steatosis, oxidative stress, apoptosis, and inflammation, contribute to NASH development. Gallic acid (GA), a natural polyphenol, was reported to exert a protective effect on hepatic steatosis in animal models, but the precise molecular mechanisms remain unclear. Here, we examined the effect of GA on hepatic lipid accumulation, apoptosis, and inflammatory response caused by hepatocyte–macrophage crosstalk. We demonstrated that GA attenuated palmitic acid (PA)-induced fat accumulation via the activation of AMP-activated protein kinase (AMPK) in HepG2 cells. GA also ameliorated cell viability and suppressed apoptosis-related gene expression and caspase 3/7 activity induced by PA and H2O2. In a co-culture of lipid-laden Hepa 1-6 hepatocytes and RAW 264 macrophages, GA reduced inflammatory mediator expression and induced antioxidant enzyme expression. These results indicate that GA suppresses hepatic lipid accumulation, apoptosis, and inflammation caused by the interaction between hepatocytes and macrophages. The potential effects of GA observed in our study could be effective in preventing NASH and its 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.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

scholarly journals E3 ubiquitin ligase Grail promotes hepatic steatosis through Sirt1 inhibition

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Pei-Yao Liu ◽  
Cheng-Cheung Chen ◽  
Chia-Ying Chin ◽  
Te-Jung Liu ◽  
Wen-Chiuan Tsai ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Acid Synthesis ◽  
Sirtuin 1 ◽  
Nonalcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Hepatic Fat ◽  
Underlying Mechanisms

AbstractIn obese adults, nonalcoholic fatty liver disease (NAFLD) is accompanied by multiple metabolic dysfunctions. Although upregulated hepatic fatty acid synthesis has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are yet to be elucidated. In this study, we reported upregulated expression of gene related to anergy in lymphocytes (GRAIL) in the livers of humans and mice with hepatic steatosis. Grail ablation markedly alleviated the high-fat diet-induced hepatic fat accumulation and expression of genes related to the lipid metabolism, in vitro and in vivo. Conversely, overexpression of GRAIL exacerbated lipid accumulation and enhanced the expression of lipid metabolic genes in mice and liver cells. Our results demonstrated that Grail regulated the lipid accumulation in hepatic steatosis via interaction with sirtuin 1. Thus, Grail poses as a significant molecular regulator in the development of NAFLD.

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