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FB2026_01
,
released March 12, 2026
ABHD5 (α/β-hydrolase domain-containing 5, also known as CGI-58) interacts with the mammalian adipose triglyceride lipase (ATGL) encoded by PNPLA1, a member of the PNPLA family of lipid storage regulators. Mutations in combinations of ABHD5 and the PNPLA family of genes are responsible for multiple neutral lipid storage diseases, as well as dysfunction in the liver, muscle, and intestine based on errors in lipid signaling or metabolism. These phenotypes, while all related to lipid signaling or processing, are not all pro-obesity -- the reduction of Abhd5 in mice, for example, actually prevents high-fat diet-induced obesity.
The human gene Hsap\ABHD5 has been introduced to Drosophila, but no investigations using this construct have been published.
The Drosophila homolog of ABHD5 and its paralog ABHD4 is the phospholipase puml. Mutants lacking puml show increased lipogenesis and overall body fat, fitness deficits (decreased climbing capability), and abnormal lipid storage in the Malphigian tubules. However, unlike in humans, puml did not stimulate the triglyceride lipase activity of bmm, an ortholog of the human PNPLA genes.
Loss-of-function mutants of bmm also exhibit obesity, see 'obesity, susceptibility to (postulated), PNPLA/ATGL-related' (FBhh0000504). ABHD5 is also linked to Chanarin-Dorfman syndrome (MIM:275630).
[updated November 2019 by FlyBase; FBrf0222196]
When challenged with a high-fat diet (HFD), Abhd5 antisense oligonucleotide-treated mice were protected against diet-induced obesity, but their hepatic contents of triglyceride (TG), diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, high-fat diet fed, Abhd5 antisense oligonucleotide-treated mice were more glucose tolerant and insulin sensitive. (Adapted from Brown et al. 2010, pubmed:20802159.)
BHD5 (α/β-hydrolase domain-containing 5) is one member of the paralogous protein pair, α/β-hydrolase domain-containing 4 (ABHD4) and ABHD5. In contrast to ABHD5, the paralogous ABHD4 is an active lipid hydrolase, which is involved in anoikis resistance and endocannabinoid biosynthesis. (Adapted from Hehlert et al. 2019 and references therein, FBrf0243095.)
In mature adipocytes, ABHD5 resides primarily on cytosolic lipid droplets. During catecholamine-stimulated lipolysis, cAMP-activated protein kinase A (PKA) phosphorylates ABHD5, facilitating the release of ABHD5 from the lipid droplet surface where it can subsequently interact with the major TAG hydrolase adipose triglyceride lipase (ATGL), also known as patatin-like phospholipase domain containing 2 (PNPLA2). (Adapted from Brown & Brown 2017 and references therein, pubmed:28827091.)
Many to one: 2 human genes to 1 Drosophila gene.