How does your fat affect your liver when you drink?

Hwang, Seonghwan; Gao, Bin

doi:10.1172/jci128984

Cited by 7 publications

(9 citation statements)

References 27 publications

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“…The contribution of adipose tissues to AALD has been recognized previously, which is receiving more attention recently because of the current global epidemic of obesity. 34 , 35 Alcohol causes WAT dysfunction by increasing lipolysis and adipocyte death, which leads to pathologic release of FFAs and inflammatory mediators. 36 In contrast, although alcohol has been known to increase the mass and oxidative capacity of BAT dozens of years ago, 37 , 38 the role of BAT in the development of AALD still is unclear.…”

Section: Discussionmentioning

confidence: 99%

Bile Acid–Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice

Fan

Wang

Jin

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Alcohol-associated liver disease (AALD) is one of the most common causes of liver injury and failure. Limited knowledge of the mechanisms underlying AALD impedes the development of efficacious therapies. Bile acid (BA) signaling was shown to participate in the progression of AALD. However, the mechanisms remain poorly understood. Methods C57BL/6J wild-type (WT), Takeda G-protein–coupled bile acid receptor 5 (TGR5) knockout (KO) and brown adipose tissue (BAT)-specific TGR5 knockdown mice were subjected to ethanol feeding–induced AALD. Liver samples from alcoholic hepatitis patients were used to examine the BA circulation signaling. Human Embryonic Kidney Cells 293 were used for the TGR5 reporter assay. 23(S)-methyl-lithocholic acid was used as a molecular tool to confirm the regulatory functions of BAT in the AALD mouse model. Results Ethanol feeding increased the expression of the thermogenesis genes downstream of TGR5 in BAT of WT, but not TGR5 KO, mice. TGR5 deficiency significantly blocked BAT activity and energy expenditure in mice after ethanol feeding. Alcohol increased serum BA levels in mice and human beings through altering BA transportation, and the altered BAs activated TGR5 signaling to regulate metabolism. Compared with ethanol-fed WT mice, ethanol-fed TGR5 KO mice showed less free fatty acid (FFA) β-oxidation in BAT, leading to higher levels of FFA in the circulation, increased liver uptake of FFAs, and exacerbated AALD. BAT-specific TGR5 knockdown mice showed similar results with TGR5 KO mice in AALD. Agonist treatment significantly activated TGR5 signaling in BAT, increased thermogenesis, reduced serum FFA level, and ameliorated hepatic steatosis and injury in AALD mice, while these effects were lost in TGR5 KO mice. Conclusions BA signaling plays a protective role in AALD by enhancing BAT thermogenesis. Targeting TGR5 in BAT may be a promising approach for the treatment of AALD.

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Section: Discussionmentioning

confidence: 99%

Bile Acid–Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice

Fan

Wang

Jin

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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“…Alcohol is well known to induce adipose lipolysis, which may involve cell death and β-adrenergic receptor activation. [9,[13][14][15][16][17] We have demonstrated previously that FAT-KO mice are defective in cold-stimulated and β3adrenergic receptor agonist-stimulated adipose lipolysis. [11] To determine how FAT-KO mice respond to ethanol-induced adipose lipolysis, we measured HSL phosphorylation at serine 660, a marker for stimulated adipose lipolysis, and ATGL, the rate-limiting enzyme of adipose lipolysis.…”

Section: Ethanol Feeding Increases Plasma Fa Concentrations In An Adi...mentioning

confidence: 99%

Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding

et al. 2022

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Background and Aims: Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis.Approach and Results: Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and

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“…Previous studies have reported that alcohol consumption causes hypothermia in human 57 and rodents maintained at 20~22 °C temperature 58 , 59 . In addition, alcohol feeding was shown to affect brown adipose tissue mass 60 and inter-organ cross talk influencing liver function 61 , 62 . Mice housed and maintained at thermoneutral conditions show greater non-alcoholic fatty liver disease and provide the best way to investigate the cellular and molecular mechanisms underpinning alcohol liver disease pathogenesis 63 .…”

Section: Methodsmentioning

confidence: 99%

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

et al. 2023

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Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

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How does your fat affect your liver when you drink?

Cited by 7 publications

References 27 publications

Bile Acid–Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice

Bile Acid–Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice

Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

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