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Investigating dual inhibition of ACC and CD36 for the treatment of non-alcoholic fatty liver disease in mice.
American Journal of Physiology. Endocrinology and Metabolism 2023 January 12
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Dysregulation in hepatic lipid metabolism, including increased fatty acid uptake and de novo lipogenesis (DNL), is a hallmark of NAFLD. Here, we investigated dual inhibition of the fatty acid transporter fatty acid translocase (FAT/CD36), and acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in DNL, for the treatment of NAFLD in mice. Mice with hepatic CD36 deletion (Cd36LKO ) and wildtype littermates were fed a high fat diet for 12 weeks and treated daily with either oral administration of an ACC inhibitor (GS-834356, Gilead Sciences, ACCi) or vehicle for 8 weeks. Neither CD36 deletion or ACC inhibition impacted body composition, energy expenditure, or glucose tolerance. Cd36LKO mice had elevated fasting plasma insulin, suggesting mild insulin resistance. Whole-body fatty acid oxidation was significantly decreased in Cd36LKO mice. Liver triglyceride content was significantly reduced in mice treated with ACCi, however, CD36 deletion caused an unexpected increase in liver triglycerides. This was associated with upregulation of genes and proteins of DNL, including ACC, and decreased liver triglyceride secretion ex vivo. Overall, these data confirm the therapeutic utility of ACC inhibition for steatosis resolution but indicate that inhibition of CD36 is not an effective treatment for NAFLD in mice.
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