Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance

Cell Rep. 2017 Jan 17;18(3):636-646. doi: 10.1016/j.celrep.2016.12.070.

Abstract

Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.

Keywords: activity-based protein profiling; carboxylesterase; diacylglycerol; hepatic steatosis; inflammation; insulin resistance; lipidomics; obesity; serine hydrolase.

MeSH terms

  • Animals
  • Carboxylesterase / antagonists & inhibitors
  • Carboxylesterase / genetics
  • Carboxylesterase / metabolism*
  • Carboxylic Ester Hydrolases / antagonists & inhibitors
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism
  • Cells, Cultured
  • Diet, High-Fat
  • Diglycerides / metabolism*
  • Endoplasmic Reticulum Stress
  • Genetic Vectors / genetics
  • Genetic Vectors / metabolism
  • Glucose / metabolism
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / pathology*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance
  • Lipid Peroxidation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism
  • Obesity / pathology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • 1,2-diacylglycerol
  • Diglycerides
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • TOR Serine-Threonine Kinases
  • AADAC protein, human
  • Carboxylic Ester Hydrolases
  • CES2 protein, human
  • Carboxylesterase
  • Glucose