ABHD5—A Regulator of Lipid Metabolism Essential for Diverse Cellular Functions

Abstract

The α/β-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.

Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58

“…Interestingly, mutations in the human gene of the ATGL coactivator CGI-58 cause severe hepatic steatosis and systemic TG accumulation that is always associated with ichthyosis ( 7 , 24 ). Analogously, global CGI-58 KO mice suffer from a lethal skin permeability barrier defect due to impaired ω-O-acylceramide synthesis ( 21 , 25 , 26 , 27 ).…”

Review article: Hepatic steatosis and its associations with acute and chronic liver diseases

“…Perilipin and ADRP associate with CGI‐58, also known as ABHD5, a co‐activator of adipose triglyceride lipase (ATGL), on the LD membrane monolayer 80 . The gene encoding CGI‐58, ABHD5 , is mutated in neutral lipid storage disease with ichthyosis, causing accumulation of triglycerides and possibly impairment in phospholipid metabolism 81,82 . CGI‐58 is also a lysophosphatidic acid acyltransferase 83 .…”

The role of lipid droplet associated proteins in inherited human disorders

“…An important clinical difference in the disease manifestations of these disorders is the presence of ichthyosis (scaly, itchy red skin) in cases caused by ABHD5 mutations [5]. This is thought to relate to disruption of the role of ABHD5 in activating PNPLA1 to catalyze the esterification of ω‐hydroxyceramides with linoleic acid in skin cells [6].…”