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

Jihong Lian,Russell Watts,Ariel D Quiroga,Megan R Beggs,R Todd Alexander,Richard Lehner

doi:10.1194/jlr.m092544

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated DNL, WT and Ces1d-deficient mice were fed a lipogenic high-sucrose diet (HSD). We found that Ces1d-deficient mice were protected from HSD-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.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease
These data suggest that the lower weight gain observed in the Ces1d / mice could be at least partially derived from decreased white adipose tissue (WAT) depots compared with WT mice
The major finding in this study is that Ces1d deficiency prevents highsucrose diet (HSD)-induced liver lipid accumulation in vivo

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat dietinduced hepatic steatosis. We found that Ces1d-deficient mice were protected from HSD-induced hepatic lipid accumulation. Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation. Loss of Ces1d enhances insulin sensitivity and protects from high-fat dietinduced liver steatosis by increasing FA oxidation and decreasing hepatic DNL [16]. To investigate whether ablation of Ces1d expression can alleviate steatosis induced by over-activated lipogenesis, we challenged Ces1d-deficient mice with a high-sucrose diet (HSD). We show that Ces1d deficiency protects against highcarbohydrate-induced liver lipid accumulation by inhibiting the key lipogenic enzyme, acetyl-CoA carboxylase (ACC)

Methods

Results

Conclusion