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

Endocrinology. 2016 Feb;157(2):570-85. doi: 10.1210/en.2015-1866. Epub 2015 Dec 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / genetics*
  • CD36 Antigens / metabolism
  • Diet, High-Fat*
  • Fatty Acids, Nonesterified / metabolism
  • Hepatocytes / metabolism*
  • Insulin Resistance / genetics*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Organ Specificity / genetics
  • Triglycerides / metabolism


  • CD36 Antigens
  • Fatty Acids, Nonesterified
  • Triglycerides