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

Abstract

liver failure ( 2 ). As a fi rst stage in the ALD spectrum, alcoholic steatosis has been extensively studied in humans and animal models to better understand the mechanisms leading to fat accumulation in the alcohol-exposed liver. This research has indicated that alcohol has many effects on hepatic lipid metabolism, including dysregulation of pathways associated with fatty acid (FA) synthesis, uptake, and oxidation, and triglyceride (TG) synthesis and export; however, the mechanisms underpinning these changes and their relative importance are only beginning to be understood ( 3 ).CD36 (also known as fatty acid translocase) is a class B scavenger receptor that is expressed on the cell surface and can recognize multiple ligands, including long-chain fatty acids, oxidized lipids, and lipoproteins ( 4 ). CD36 has multiple cell type-specifi c physiological functions; for example, its expression in microvascular endothelial cells is associated with angiogenesis, and in the apical cells of taste buds, it is associated with the detection of dietary fatty acids ( 4, 5 ). CD36 is also a mediator of free fatty acid (FFA) uptake into tissues, particularly adipose, heart, and skeletal muscle ( 6, 7 ). It is thought that CD36 does not normally play a signifi cant role in hepatic FFA uptake; however, under nonphysiological conditions, CD36 is induced in the liver and may contribute to hepatic steatosis ( 6 ). For example, pharmacologic activation of liver X receptors increases CD36 expression and TG accumulation in the liver ( 8 ), adenoviral-mediated overexpression of hepatic CD36 increases FFA uptake and TG accumulation ( 9 ), and liver tissues obtained from patients with nonalcoholic fatty liver disease also have significantly elevated CD36 expression ( 10 ).Our group and others have observed increased hepatic CD36 expression in alcohol-fed mice at the gene and protein levels ( 11-13 ). Given the role of CD36 in facilitating FFA uptake into tissues and the observation that it is upregulated in the alcohol-exposed liver, we hypothesized that CD36 is Abstract CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36 -defi cient ( Cd36 ؊ / ؊ ) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36 ؊ / ؊ mice would be resistant to alcoholic steatosis. Our data show that the livers of Cd36 ؊ / ؊ mice are resistant to the lipogenic effect of consuming highcarbohydrate liquid diets. These mice also do not further develop alcoholic steatosis when chronically fed alcohol. Surprisingly, we did not detect an effect of alcohol or CD36 deficiency on hepatic FFA uptake; however, the lower baseline levels of hepatic TG in ...

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

“…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].…”

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

“…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.…”

Alcohol, Adipose Tissue and Lipid Dysregulation

“…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.…”

“…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]. …”