Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members

Andrew C Lake,Ying Sun,Jian-Liang Li,Jae Eun Kim,Jeremy W Johnson,Dongmei Li,Tracy Revett,Heather H Shih,Wei Liu,Janet E Paulsen,Ruth E Gimeno

doi:10.1194/jlr.m500290-jlr200

Abstract

Adiponutrin and a related protein, adipocyte triglyceride lipase (ATGL; also known as Desnutrin), were recently described as adipocyte-specific proteins with lipid hydrolase activity. Using bioinformatics, we identified three additional Adiponutrin family members (GS2, GS2-Like, and PNPLA1). Here, we report on the expression, regulation, and activity of GS2 and GS2-Like compared with Adiponutrin and Desnutrin/ATGL. GS2-Like is expressed and regulated in a manner similar to Adiponutrin; however, the absolute levels of mRNA are significantly lower than those of Adiponutrin or Desnutrin/ATGL. GS2 transcripts were identified only in humans and are highly expressed in adipose as well as other tissues. All four proteins show lipase activity in vitro, which is dependent on the presence of the active site serine for Adiponutrin, Desnutrin/ATGL, and GS2. Overexpression of Desnutrin/ATGL, GS2, and GS2-Like, but not Adiponutrin, decreases intracellular triglyceride levels. This is consistent with a function for Desnutrin/ATGL, GS2, and GS2-Like in lipolysis, but not for Adiponutrin. Consistent with previously reported data, Desnutrin/ATGL is upregulated by fasting in adipose tissue, whereas Adiponutrin is downregulated. Additionally, Adiponutrin and GS2-Like, but not Desnutrin/ATGL, are strongly induced in the liver of ob/ob mice. Our data support distinct functions for Adiponutrin and Desnutrin/ATGL and raise the possibility that GS2 may contribute significantly to lipolysis in human adipose tissue.

Highlights

Adiponutrin and a related protein, adipocyte triglyceride lipase (ATGL; known as Desnutrin), were recently described as adipocyte-specific proteins with lipid hydrolase activity
The presence of significant residual lipolysis in adipose tissue of hormone-sensitive lipase (HSL)-null mice suggested the existence of an additional triglyceride lipase, and recently, a candidate for this activity, adipocyte triglyceride lipase (ATGL; known as Desnutrin), was identified and shown to be responsible for most, if not all, lipolysis remaining in HSLnull mice [11, 12]
In contrast to Desnutrin/ATGL, whose expression is upregulated under conditions of increased lipolysis, Adiponutrin mRNA dramatically decreases in adipose tissue during fasting [15,16,17,18]

Summary

Introduction

Adiponutrin and a related protein, adipocyte triglyceride lipase (ATGL; known as Desnutrin), were recently described as adipocyte-specific proteins with lipid hydrolase activity. The presence of significant residual lipolysis in adipose tissue of HSL-null mice suggested the existence of an additional triglyceride lipase, and recently, a candidate for this activity, adipocyte triglyceride lipase (ATGL; known as Desnutrin), was identified and shown to be responsible for most, if not all, lipolysis remaining in HSLnull mice [11, 12]. Desnutrin/ATGL is most closely related to Adiponutrin, an adipocyte-specific protein of unknown function that recently was shown to have lipid hydrolase activity [13]. Both Adiponutrin and Desnutrin/ATGL contain an N-terminal patatin-like domain that includes a conserved catalytic dyad [Gly-X-Ser-X-Gly and Asp-X-Gly/ Ala [14]]. Two additional Adiponutrin-related genes have been identified in the literature [13, 19]; their expression pattern in adipose tissue and function have not yet been examined, and the existence of other Adiponutrin family members is unclear

Methods

Results

Conclusion