An Epistatic Interaction between Pnpla2 and Lipe Reveals New Pathways of Adipose Tissue Lipolysis.

Xiao Zhang,Hao Yang,Grant A Mitchell,Cong Cong Zhang,Shu Pei Wang,Jiang Wei Wu,Krishnakant G Soni

doi:10.3390/cells8050395

Abstract

White adipose tissue (WAT) lipolysis contributes to energy balance during fasting. Lipolysis can proceed by the sequential hydrolysis of triglycerides (TGs) by adipose triglyceride lipase (ATGL), then of diacylglycerols (DGs) by hormone-sensitive lipase (HSL). We showed that the combined genetic deficiency of ATGL and HSL in mouse adipose tissue produces a striking different phenotype from that of isolated ATGL deficiency, inconsistent with the linear model of lipolysis. We hypothesized that the mechanism might be functional redundancy between ATGL and HSL. To test this, the TG hydrolase activity of HSL was measured in WAT. HSL showed TG hydrolase activity. Then, to test ATGL for activity towards DGs, radiolabeled DGs were incubated with HSL-deficient lipid droplet fractions. The content of TG increased, suggesting DG-to-TG synthesis rather than DG hydrolysis. TG synthesis was abolished by a specific ATGL inhibitor, suggesting that ATGL functions as a transacylase when HSL is deficient, transferring an acyl group from one DG to another, forming a TG plus a monoglyceride (MG) that could be hydrolyzed by monoglyceride lipase. These results reveal a previously unknown physiological redundancy between ATGL and HSL, a mechanism for the epistatic interaction between Pnpla2 and Lipe. It provides an alternative lipolytic pathway, potentially important in patients with deficient lipolysis.

Highlights

Adipose tissue lipolysis degrades triglycerides (TGs), releasing fatty acids and glycerol
ATGLAKO mice were homozygous for a floxed allele of the Pnpla2 gene and harbored a transgene, from which Cre is expressed from a Fabp4 promoter, which is active in adipose tissues
We recently showed that an epistatic interaction exists between the Pnpla2 and Lipe genes that encode adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), respectively [3]

Summary

Introduction

Adipose tissue lipolysis degrades triglycerides (TGs), releasing fatty acids and glycerol. Lipolysis is crucial for energy homeostasis, especially under fasting conditions. Abnormalities of lipolysis have been related to multiple components of metabolic syndrome, including obesity, fatty liver and diabetes [1,2,3,4]. Lipolysis has been extensively studied, especially in white adipose tissue (WAT) [2,3,12,13,14]. A view has emerged of lipolysis as a linear pathway catalyzed by three enzymes: adipose triglyceride lipase (ATGL) [15], hormone-sensitive lipase (HSL) [16] and monoglyceride lipase (MGL) [17].

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Results

Conclusion