Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. TG accumulation in liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase 1d (Ces1d) expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated de novo lipogenesis, wild type and Ces1d deficient mice were fed a lipogenic high-sucrose diet. We found that Ces1d deficient mice were protected from high-sucrose diet-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency leads to activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase. Together with our previous demonstration that Ces1d deficiency attenuated high-fat diet-induced steatosis, this study suggests that inhibition of CES1 (the human ortholog of Ces1d) might represent a novel pharmacological target for prevention and treatment of NAFLD.