ABHD5

ABHD5, also known as CGI-58 (comparative gene identification-58), is a human protein encoded by the ABHD5 gene. It belongs to the alpha/beta hydrolase domain-containing family but lacks classical catalytic activity, functioning instead as a coactivator for triglyceride lipolysis. The gene is located on chromosome 3p21.31 and the protein is expressed in many tissues, with prominent roles in adipose tissue and other metabolically active organs.

Function and mechanism

ABHD5 acts as a coactivator of adipose triglyceride lipase (ATGL, also called PNPLA2), stimulating the hydrolysis of stored triglycerides within lipid droplets to release free fatty acids and glycerol. It is associated with lipid droplets and interacts with ATGL to promote lipolysis in adipocytes and non-adipose cells. In adipocytes, hormonal signaling that phosphorylates perilipin-1 (PLIN1) facilitates the mobilization of ABHD5 from the perilipin-coated lipid droplet surface to activate ATGL, thereby enhancing fatty acid mobilization.

Clinical significance

Mutations in ABHD5 cause Chanarin-Dorfman syndrome, also known as neutral lipid storage disease with ichthyosis (NLSDI). This autosomal recessive disorder is characterized by accumulation of neutral lipids in multiple tissues, including skin (ichthyosis), liver, and muscle, and can present with lipid-laden leukocytes known as Jordan’s anomaly. Other NLSD forms are linked to mutations in PNPLA2 (NLSDM). Diagnosis combines clinical features with genetic testing for ABHD5 mutations.

Structure and regulation

ABHD5 is part of the alpha/beta hydrolase fold family but lacks a functional catalytic serine, reflecting its role as a regulatory cofactor rather than an enzyme. It is regulated by cellular lipid-droplet dynamics and hormonal signals that control ATGL activity, with ABHD5 activity closely tied to perilipin-1–mediated lipolytic signaling.