Critical roles for α/β hydrolase domain 5 (ABHD5)/comparative gene identification-58 (CGI-58) at the lipid droplet interface and beyond

Abstract

Mutations in the gene encoding comparative gene identification 58 (CGI-58), also known as α β hydrolase domain-containing 5 (ABHD5), cause neutral lipid storage disorder with ichthyosis (NLSDI). This inborn error in metabolism is characterized by ectopic accumulation of triacylglycerols (TAG) within cytoplasmic lipid droplets in multiple cell types. Studies over the past decade have clearly demonstrated that CGI-58 is a potent regulator of TAG hydrolysis in the disease-relevant cell types. However, despite the reproducible genetic link between CGI-58 mutations and TAG storage, the molecular mechanisms by which CGI-58 regulates TAG hydrolysis are still incompletely understood. It is clear that CGI-58 can regulate TAG hydrolysis by activating the major TAG hydrolase adipose triglyceride lipase (ATGL), yet CGI-58 can also regulate lipid metabolism via mechanisms that do not involve ATGL. This review highlights recent progress made in defining the physiologic and biochemical function of CGI-58, and its broader role in energy homeostasis. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.

Keywords: ABHD5; ATGL; Adipocyte; CGI-58; Lipase; Triacylglycerol.

Fig. 1

The role of CGI-58 in adipocyte lipolysis. Under basal conditions, CGI-58 interacts with perilipin 1 (PLIN1) at the lipid droplet surface, where it is tethered away from interactions with the triacylglycerol (TAG) lipase adipose triglyceride lipase (ATGL). Upon catecholamine stimulation, elevations in cellular cyclic AMP activate protein kinase A (PKA), which then phosphorylates the diacylglycerol (DAG) lipase, hormone sensitive lipase (HSL), and also PLIN1 and CGI-58. PKA-mediated phosphorylation of HSL facilitates its translocation from the cytosol to the lipid droplet surface, while phosphorylation of PLIN and CGI-58 causes dissociation of these two proteins and subsequent interaction of CGI-58 and ATGL to drive TAG hydrolysis.

Fig. 2

The role of CGI-58 in skeletal muscle metabolism and transcriptional regulation of mitochondrial function. Non-esterified fatty acids (NEFA) are delivered to skeletal muscle either complexed to albumin or via lipoprotein lipase-driven lipolysis of triglyceride-rich lipoproteins (TGRLP), and taken up into the cell helped by fatty acid transport proteins (FATPs) or the scavenger receptor cluster of differentiation 36 (CD36). Once inside the cell, a portion of newly delivered NEFA are activated into fatty acyl-coenzyme A (FA-CoA) molecules and either used for oxidative fuel in the mitochondria or are esterifed into triacylglycerols (TAG) via the action of diacylglycerol acyltransferase (DGAT) enzymes. At the lipid droplet surface CGI-58 co-activates adipose triglyceride lipase (ATGL) to promote hydrolysis of TAG, and the liberated NEFAs and other acylglycerol lipolysis products are delivered to either the mitochondria for oxidation or the nucleus to activate peroxisome proliferator-activated receptor α (PPARα) signaling to further drive oxidative gene expression.

Fig. 3

The role of CGI-58 in plant lipid metabolism and signaling. In the model plant organism Arabidopsis thaliana CGI-58 directly interacts with the peroxisomal ATP-binding cassette transporter PXA1. These proteins collaborate to promote transport of non-esterified fatty acids (NEFA) to provide energy and also stimulate the transport of key intermediate metabolites that are critical for plant hormone production. First, the interaction between CGI-58 and PXA1 facilitates the transport and β-oxidation of NEFA in peroxisomes. In parallel, CGI-58 facilitates PXA1-dependent transport of the plant hormone lipid intermediates 12-oxo phytodienoic acid (OPDA) and indole butyric acid (IBA) into the peroxisome where they are converted, respectively, to jasmonic acid or indole acetic acid, which are key regulatory hormones in plants promoting pathogen resistance and growth.