CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Clugston, Robin D.; Yuen, Jason J.; Hu, Yixin; Abumrad, Nada A.; Berk, Paul D.; Goldberg, Ira J.; Blaner, William S.; Huang, Li‐Shin

doi:10.1194/jlr.m041863

Cited by 66 publications

(62 citation statements)

References 42 publications

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“…Although CD36/FAT does not play a major role in fatty acid uptake in normal liver [40,41], increased hepatic CD36/FAT expression has been observed in various pathologic conditions such as cancer, NAFLD, and type 2 diabetes mellitus [42,43]. Similarly, CD36/FAT levels were up-regulated in CerS2 null mice, although CD36/FAT was non-functional since it was mis-localized, likely due to altered membrane properties [12,14,16].…”

Section: Discussionmentioning

confidence: 99%

Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length

Park

Merrill

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Ceramide synthase 2 (CerS2) null mice cannot synthesize very-long acyl chain (C22-C24) ceramides resulting in significant alterations in the acyl chain composition of sphingolipids. We now demonstrate that hepatic triacylglycerol (TG) levels are reduced in liver but not in adipose tissue or skeletal muscle in the CerS2 null mouse, both before and after feeding with a high fat diet (HFD), where no weight gain was observed and large hepatic nodules appeared. Uptake of both BODIPY-palmitate and [3H]-palmitate were also abrogated in hepatocytes and liver. The role of a number of key proteins involved in fatty acid uptake was examined, including FATP5, CD36/FAT, FABPpm and cytoplasmic FABP1. Levels of FATP5 and FABP1 were decreased in CerS2 null mouse liver, whereas CD36/FAT levels were significantly elevated and CD36/FAT was also mislocalized upon insulin treatment. Moreover, treatment of hepatocytes with C22-C24-ceramides down-regulated CD36/FAT levels. Infection of CerS2 null mice with recombinant adeno-associated virus (rAAV)-CerS2 restored normal TG levels and corrected the mislocalization of CD36/FAT, but had no effect on the intracellular localization or levels of FATP5 or FABP1. Together, these results demonstrate that hepatic fatty acid uptake via CD36/FAT can be regulated by altering the acyl chain composition of sphingolipids.

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Section: Discussionmentioning

confidence: 99%

Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length

Park

Merrill

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Indeed, CD36, the fatty acid translocase, is upregulated in mice lacking ACE2 (Figure 3). It has been shown that the upregulation of CD36 in the liver is associated with increased steatosis in NAFLD patients [29, 30] and CD36 −/− mice are resistant to alcohol and high carbohydrate-induced hepatic steatosis [31]. Moreover, in mice and humans aging increases CD36 membrane expression in the liver [29], causing increased fat uptake and advancing NAFLD with age.…”

Section: Discussionmentioning

confidence: 99%

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2‐Deficient Mice

Nunes-Souza

Alenina

Qadri

et al. 2016

Oxidative Medicine and Cellular Longevity

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Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2−/y) mice. Methods. Male C57BL/6 and ACE2−/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2−/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2−/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2−/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2−/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis.

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“…Alcohol also modulates the expression of lipoprotein receptors in the liver to regulate uptake of fatty acids released from the adipose tissue. Accordingly, chronic alcohol intake increased CD36 [7,57,58,59] and very low density lipoprotein receptor (VLDLR) expression in the liver [60], whereas knock-out of these receptors protected mice from the development of alcohol-induced fatty liver [57,60]. In contrast, chronic alcohol intake decreased VLDLR and LPL [60] and did not change CD36 expression in WAT [7], indicating differential regulation between tissues and potentiation of the lipolytic phenotype induced by alcohol.…”

Section: Regulation Of Lipid Balancementioning

confidence: 99%

“…In contrast, the effects of alcohol on the expression of FATPs in the liver are inconsistent and differ with each form. FATP1 has been reported to be increased [61], decreased [58], and unchanged [57,59]; similarly, changes in FATP2 and FATP5 are also variable within and across studies in chronic alcohol-fed animals [7,57,58,59,61]. …”

Section: Regulation Of Lipid Balancementioning

confidence: 99%

Alcohol, Adipose Tissue and Lipid Dysregulation

Steiner

Lang

2017

Biomolecules

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Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids in liver steatosis, alcohol also impacts other functions of adipose tissue and lipid metabolism. Lipid balance in response to long-term alcohol intake favors adipose tissue loss and fatty acid efflux as lipolysis is upregulated and lipogenesis is either slightly decreased or unchanged. Study of the lipolytic and lipogenic pathways has identified several regulatory proteins modulated by alcohol that contribute to these effects. Glucose tolerance of adipose tissue is also impaired by chronic alcohol due to decreased glucose transporter-4 availability at the membrane. As an endocrine organ, white adipose tissue (WAT) releases several adipokines that are negatively modulated following chronic alcohol consumption including adiponectin, leptin, and resistin. When these effects are combined with the enhanced expression of inflammatory mediators that are induced by chronic alcohol, a pro-inflammatory state develops within WAT, contributing to the observed lipodystrophy. Lastly, while chronic alcohol intake may enhance thermogenesis of brown adipose tissue (BAT), definitive mechanistic evidence is currently lacking. Overall, both WAT and BAT depots are impacted by chronic alcohol intake and the resulting lipodystrophy contributes to fat accumulation in peripheral organs, thereby enhancing the pathological state accompanying chronic alcohol use disorder.

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CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Cited by 66 publications

References 42 publications

Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length

Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2‐Deficient Mice

Alcohol, Adipose Tissue and Lipid Dysregulation

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