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.

Keywords: ABHD5; ATGL; CGI-58; Chanarin-Dorfman syndrome; NAFLD; NLSD; PNPLA3; ichthyosis; lipid metabolism; triglyceride.

Figure 1

Protein domain organization of human α/β hydrolase domain containing protein 5 (ABHD5). The α/β-hydrolase domain (dark green box), located at the carboxyl terminus of the protein, contains the predicted catalytic triad (indicated in blue) consisting of the consensus GxSxG lipase motif in which the serine is replaced by an asparagine residue (Asn153), and Asp301 as well as His327 within the conserved Hx4D acyltransferase motif. At the amino terminus, ABHD5 harbors a tryptophan (Trp)-rich region (light green box) important for lipid droplet binding.

Figure 2

Similarities and differences in the clinical manifestations of Neutral Lipid Storage Disease with Myopathy (NLSDM) vs. Neutral Lipid Storage Disease with Ichthyosis (NLSDI). Mutations in the gene encoding adipose triglyceride lipase (ATGL) cause NLSDM, while mutations in the gene coding for α/β hydrolase domain containing protein 5 (ABHD5) are associated with NLSDI. Both syndromes are characterized by systemic triacylglycerol accumulation and Jordans’ anomaly, which describes an accumulation of lipid-containing vacuoles in leukocytes. While NLSDM is associated with severe forms of cardiac myopathy, patients with NLSDI always suffer from ichthyosis. In addition, NLSDM patients often show clinical manifestations of skeletal myopathy and less commonly hepatomegaly, liver steatosis, or reduced insulin secretion rates. In contrast, NLSDI patients often suffer from liver steatosis, hepatomegaly, and neurological disorders and rarely from skeletal myopathy.

Figure 3

Generation of branched fatty acid esters of hydroxy fatty acids by transacylase activity of adipose triglyceride lipase. Adipose triglyceride lipase (ATGL) catalyzes the transfer of fatty acids (FAs, FA chain colored in blue) from triacylglycerol (TAG) or diacylglycerol (DAG) molecules onto hydroxy fatty acids (HFAs, HFA chain colored in orange), resulting in fatty acid esters of hydroxy fatty acids (FAHFAs).

Figure 4

Molecular structure of triacylglycerol estolide. Adipose triglyceride lipase (ATGL, co-activated by α/β hydrolase domain containing protein 5, ABHD5) and hormone-sensitive lipase (HSL) show different substrate specificities towards ester bonds in triacylglycerol estolide molecules as indicated by arrows.

Figure 5

Schematic representation of basal and stimulated lipolysis in adipose tissue. Under basal conditions, perilipin 1 (PLIN1) binds α/β hydrolase domain containing protein 5 (ABHD5) and prevents the interaction of ABHD5 with adipose triglyceride lipase (ATGL), thereby suppressing lipolysis. ATGL, hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL) are primarily located in the cytosol; however, low levels of ATGL are associated with lipid droplets and enable basal lipolysis. Activation of β-adrenergic receptors (β-AR) by noradrenalin (NA), adrenocorticotropic hormone (ACTH), or secretin leads to increased adenylate cyclase (AC) activity, resulting in an increase in cAMP levels. cAMP activates protein kinase A (PKA), which phosphorylates PLIN1, ATGL, ABHD5, and HSL. The phosphorylation of PLIN1 releases phosphorylated ABHD5, which then interacts with phosphorylated ATGL to stimulate triacylglycerol (TAG) degradation. Moreover, phosphorylated PLIN1 recruits phosphorylated HSL to the surface of lipid droplets, which hydrolyzes diacylglycerol (DAG) to monoacylglycerol (MAG). In the final step of lipolysis, MGL releases the last remaining fatty acid (FA) from the glycerol backbone.

Figure 6

Molecular structure of ω-O-acylceramide. The α/β hydrolase domain containing protein 5 is involved in the esterification of ω-hydroxyceramide with linoleic acid (fatty acid chain colored in purple), producing ω-O-acylceramide. The molecular similarities between ω-O-acylceramide and triacylglycerol estolide (compared with Figure 4) are worth noting, as both molecules contain a fatty acid esterified to a hydroxy fatty acid.