Long‐term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy‐lysosomal machinery

Pi, Huifeng; Liu, Mengyu; Chen, Mengyan; Tian, Li; Xie, Jia; Chen, Mingliang; Wang, Zhen; Ye, Min; Yu, Zhengping; Zhou, Zhou; Gao, Feng

doi:10.1096/fj.201900812r

Cited by 47 publications

(32 citation statements)

References 59 publications

(69 reference statements)

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“…S3a,b). Consistent with this hypothesis, a previous study has shown that the overexpression of FABP1 in the mouse liver promotes non-alcoholic fatty liver disease [52].…”

Section: Discussionsupporting

confidence: 65%

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Costello¹,

Shin²,

Trac³

et al. 2020

Preprint

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BACKGROUND: Regulatory innovation is central to the evolution of species. Different nutritional sources are one environmental pressure that can lead to selection for novel regulatory elements. Dietary composition changes, including exposure to "western" diets with excess fat and sugar content, can lead to transcriptional regulatory changes in the liver. In order to investigate how transcriptional regulatory changes in response to a high fat diet diverge across species, we profiled chromatin accessibility, histone modifications and the transcriptome in livers of rhesus macaques and mice fed high fat and normal diets. RESULTS: While the majority of elements exhibiting changes in chromatin accessibility in response to a high fat diet are enriched for similar transcription factors across species, the loci that change are mostly species specific. These unique responsive regulatory elements are largely derived from transposable elements and are enriched for liver-specific transcription factors, such as HNF4ɑ. Furthermore, the majority of genes that respond to a high fat diet in rhesus macaques do not have a shared response in mice and are proximal to regulatory elements that display changes in chromatin accessibility only in rhesus macaques. CONCLUSIONS: Our study demonstrates that most of the liver regulatory elements that exhibit changes in chromatin accessibility in response to a high fat diet do so in a species-specific manner. These findings illustrate how a similar environmental stimulus can drive a divergent chromatin and transcriptional responses in evolutionary distinct mammalian species.

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“…S3a,b). Consistent with this hypothesis, a previous study has shown that the overexpression of FABP1 in the mouse liver promotes non-alcoholic fatty liver disease [52].…”

Section: Discussionsupporting

confidence: 65%

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Costello¹,

Shin²,

Trac³

et al. 2020

Preprint

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“…Defective lysosomal biogenesis and clearance impair autophagic flux, leading to intracellular lipid accumulation during the development of NAFLD (Chao et al, 2018b). Previous studies found that HFD disrupted lysosomal biogenesis in hepatocytes, which was associated with lipid degradation (Pi et al, 2019). We employed lysosomal inhibitor CQ to further investigate autophagy-lysosomal pathway involvement and found that liraglutide stimulated autophagic flux, as demonstrated by a reduction in autophagosome accumulation indicated by mRFP-GFP-LC3.…”

Section: Discussionmentioning

confidence: 94%

“…Lysosomes are organelles involved in the process of intracellular substrate degradation through autophagosomelysosome fusion and play a critical role in regulating autophagic flux and lipid droplet clearance. Normally, lysosomal lipid degradation capacity depends on a sufficient number of lysosomes and the activation of acid hydrolase enzymes (Sinha et al, 2014;Pi et al, 2019). Transcription factor EB (TFEB), Abbreviations: GLP-1RA, glucagon-like peptide-1 receptor agonist; NAFLD, non-alcoholic fatty liver disease; GLP-1R, glucagon-like peptide-1 receptor; PA, palmitic acid; TFEB, transcription factor EB; siRNA, small interfering RNA; LC3-II, microtubule-associated protein 1B light chain-3-II; HFD, high-fat diet; IGPTT, intraperitoneal glucose tolerance test; ITT, insulin tolerance test; TG, serum triglycerides; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; ALT, alanine transferase; AST, aspartic acid transaminase; FBS, fetal bovine serum; OA, oleic acid.…”

mentioning

confidence: 99%

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Fang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

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“…Also quercetin, a flavonoid found in various fruits and vegetables, anthocyanins from sweet cherries, and trehalose, a naturally occurring disaccharide derived from cocoons, have been reported to activate hepatic autophagy and reduce hepatic lipid content ( 115 , 116 , 124 , 125 ). In mice, long-term exercise protects against high-fat diet-induced hepatic lipid accumulation at least partly by increasing the autophagic flux ( 117 ). Fasting, intermittent fasting, caloric restriction and caloric restriction mimetic drugs all induce autophagy in various tissues including the liver and could therefore also be used as a strategy to reduce hepatic steatosis ( 118 – 120 ).…”

Section: Pre-clinical Studies On the Role Of Lipophagy In Non-alcoholmentioning

confidence: 99%

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

et al. 2021

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Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.

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Long‐term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy‐lysosomal machinery

Cited by 47 publications

References 59 publications

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

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