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.

PNPLA2 influences secretion of triglyceride-rich lipoproteins by human hepatoma cells

“…Further studies are in progress to define in more detail the subcellular localization of these proteins in Huh7 hepatoma cells. Overall, our studies support the notion that ABHD5 acts as a co-activator of PNPLA2 in Huh7 hepatoma cells, in a similar manner as proposed for the interaction of ABHD5 and PNPLA2 in human adipose tissue 36 .…”

“…Abhydrolase domain containing-5 protein (ABHD5), also known as CGI-58, is a member of an esterase/thioesterase/lipase gene family. It has been implicated in having a role in triglyceride hydrolysis, as well as in TRL assembly and secretion, via activation of PNPLA2 as investigated in adipocytes and myocytes 35,36 . Liverspecific inhibition of ABHD5 in mice has shown to induce hepatic steatosis 37,38 and reduction in triglyceride hydrolase activity and TRL secretion 37 .…”

ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier

“…To date, several studies have demonstrated an interaction of ABHD5 with proteins involved in cellular lipid and energy metabolism ( 37 ). One of the best characterized interactions is the activation of ATGL by ABHD5 that has been identified in our laboratory ( 19 ).…”

Novel Pharmacological Probes Reveal ABHD5 as a Locus of Lipolysis Control in White and Brown Adipocytes

“…Several ATGL-independent roles for ABHD5 have also been described (Lord and Brown, 2012;Brown and Brown, 2017). For example, it has been suggested that ABHD5 has tumor suppressor functions in colorectal carcinogenesis, potentially by regulating autophagic flux and AMP-activated protein kinase signaling (Ou et al, 2014;Peng et al, 2016).…”