Hepatocyte-Specific Disruption of CD36 Attenuates Fatty Liver and Improves Insulin Sensitivity in HFD-Fed Mice

Abstract

CD36/FAT (fatty acid translocase) is associated with human and murine nonalcoholic fatty liver disease, but it has been unclear whether it is simply a marker or whether it directly contributes to disease pathogenesis. Mice with hepatocyte-specific deletion of Janus kinase 2 (JAK2L mice) have increased circulating free fatty acids (FAs), dramatically increased hepatic CD36 expression and profound fatty liver. To investigate the role of elevated CD36 in the development of fatty liver, we studied two models of hepatic steatosis, a genetic model (JAK2L mice) and a high-fat diet (HFD)-induced steatosis model. We deleted Cd36 specifically in hepatocytes of JAK2L mice to generate double knockouts and from wild-type mice to generate CD36L single-knockout mice. Hepatic Cd36 disruption in JAK2L livers significantly improved steatosis by lowering triglyceride, diacylglycerol, and cholesterol ester content. The largest differences in liver triglycerides were in species comprised of oleic acid (C18:1). Reduction in liver lipids correlated with an improvement in the inflammatory markers that were elevated in JAK2L mice, namely aspartate aminotransferase and alanine transaminase. Cd36 deletion in mice on HFD (CD36L-HFD) reduced liver lipid content and decreased hepatic 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-FA uptake as compared with CON-HFD. Additionally, CD36L-HFD mice had improved whole-body insulin sensitivity and reduced liver and serum inflammatory markers. Therefore, CD36 directly contributes to development of fatty liver under conditions of elevated free FAs by modulating the rate of FA uptake by hepatocytes. In HFD-fed animals, disruption of hepatic Cd36 protects against associated systemic inflammation and insulin resistance.

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

“…Despite the well-documented function of CD36 in fatty acid uptake (41) and several reports that associate hepatic CD36 signaling with an increased risk of developing liver steatosis (3,5,6,8,42), we showed that overexpression of CD36 in the livers of our transgenic mice did not worsen metabolic functions but rather protected the mice from the detrimental metabolic changes caused by HFD feeding and prolonged fasting. The antisteatotic effect of CD36 is consistent with a report that whole-body CD36 ablation exacerbated hepatic steatosis in the ob/ob background (10) but is contrary to a recent study showing that liver-specific knockout of CD36 reduced the liver lipid content when mice were challenged with HFD (42).…”

“…The antisteatotic effect of CD36 is consistent with a report that whole-body CD36 ablation exacerbated hepatic steatosis in the ob/ob background (10) but is contrary to a recent study showing that liver-specific knockout of CD36 reduced the liver lipid content when mice were challenged with HFD (42). Future studies are necessary to explain the discrepancies in the fatty liver phenotypes between the whole-body and liver-specific CD36 knockout models.…”

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

“…Although global Cd36 knockout does not protect against high fructose-induced hepatic steatosis (Hajri, et al 2002) or prevent fatty liver in ob/ob mice (Nassir, et al 2013), a more recent report supports a liver-specific role of Cd36 in FA uptake. Specifically, congenital liver-specific Cd36 knockout reduced steatosis in liver-specific Jak2 knockout mice that led to an increase in plasma NEFA (Wilson, et al 2015). Also in that same study, liver-specific Cd36 knockout mice with intact hepatic Jak2, dramatically reduced HF-diet induced steatosis that was associated with a reduction in hepatic FA uptake as measured by hepatic accumulation of BODIPY-FA in vivo (Wilson et al 2015).…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Hyperinsulinemia alone can stimulate hepatic Cd36 expression, and is suggested as a primary mechanism driving hepatic lipid accumulation (Steneberg et al 2015). Hepatic-specific knockout of Cd36 protects mice from high-fat diet-induced fatty liver and insulin resistance, supporting the hypothesis that increased hepatic lipid uptake is critical for the development of hepatic triglyceride accumulation (Wilson et al 2016). Hepatic lipoprotein lipase (LPL) expression and activity are also increased in high-fat diet-fed mice and obese individuals, offering another mechanism for increased hepatic lipid uptake in fatty liver disease (Pardina et al 2009, Ahn et al 2011.…”