Oral Presentation ANZOS Annual Scientific Meeting 2021

Dual inhibition of CD36 and ACC is not a therapeutic approach for non-alcoholic fatty liver disease in mice. (#42)

Camille Devereux 1 , Jacqueline Bayliss 1 , Magdalene Montgomery 1 , Matthew Watt 1
  1. University of Melbourne, Melbourne, VIC, Australia

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a global prevalence of 24%. Patients with NAFLD often have insulin resistance and/or type 2 diabetes and have an increased risk for developing advanced liver disease, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and liver cancer. Despite this increasing clinical epidemic, there are currently no approved pharmacotherapies for NAFLD and NASH.

Dysregulation in lipid metabolism, including increased fatty acid uptake and de novo lipogenesis (DNL), is a hallmark of NAFLD. Here, we investigated the therapeutic potential of dual inhibition of the fatty acid transporter CD36, and acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in DNL, for the treatment of NAFLD in mice.  

Mice with hepatic CD36 deletion (CD36-LKO) and their respective wildtype littermates were fed a high fat diet for 8 weeks, in the absence or presence of daily oral administration of an ACC inhibitor (GS-834356, Gilead Sciences, ACCi). Neither CD36 deletion or ACC inhibition impacted body weight, adiposity, energy expenditure, glucose tolerance or insulin sensitivity. The respiratory exchange ratio (RER) was significantly increased in CD36-LKO mice, pointing to reduced capacity for fatty acid oxidation. ACCi-treated mice, as expected, showed a significant reduction in liver triglyceride content; however, CD36 deletion led to a mild compensatory increase in the expression of the fatty acid transport protein FATP5, and an overall increase in liver triglyceride accumulation.

 Overall, these data confirm the therapeutic utility of ACC inhibition in NAFLD but indicate that dual inhibition of CD36 and ACC is not an effective strategy for the treatment of NAFLD.