Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice

Hepatology. 2016 Jun;63(6):1860-74. doi: 10.1002/hep.28472. Epub 2016 Mar 15.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). So far, the underlying mechanism remains poorly understood. Here, we show that hepatic carboxylesterase 2 (CES2) is markedly reduced in NASH patients, diabetic db/db mice, and high-fat diet (HFD)-fed mice. Restoration of hepatic CES2 expression in db/db or HFD-fed mice markedly ameliorates liver steatosis and insulin resistance. In contrast, knockdown of hepatic CES2 causes liver steatosis and damage in chow- or Western diet-fed C57BL/6 mice. Mechanistically, we demonstrate that CES2 has triglyceride hydrolase activity. As a result, gain of hepatic CES2 function increases fatty acid oxidation and inhibits lipogenesis, whereas loss of hepatic CES2 stimulates lipogenesis by inducing endoplasmic reticulum stress. We further show that loss of hepatic CES2 stimulates lipogenesis in a sterol regulatory element-binding protein 1 (SREBP-1)-dependent manner. Finally, we show that hepatocyte nuclear factor 4 alpha (HNF-4α) plays a key role in controlling hepatic CES2 expression in diabetes, obesity, or NASH.

Conclusion: CES2 plays a protective role in development of NAFLD. Targeting the HNF-4α/CES2 pathway may be useful for treatment of NAFLD. (Hepatology 2016;63:1860-1874).

MeSH terms

  • Adiposity
  • Animals
  • Carboxylesterase / metabolism*
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism*
  • Diabetes Mellitus, Experimental / enzymology
  • Diet, High-Fat / adverse effects
  • Endoplasmic Reticulum Stress
  • Energy Metabolism
  • Gene Knockdown Techniques
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Homeostasis
  • Humans
  • Lipid Metabolism*
  • Lipogenesis
  • Lipolysis
  • Liver / enzymology
  • Male
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity / enzymology
  • Obesity / etiology
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Carboxylic Ester Hydrolases
  • CES2 protein, human
  • Carboxylesterase
  • Ces2c protein, mouse
  • Glucose