AGPAT2

AGPAT2, or 1-acylglycerol-3-phosphate acyltransferase 2, is an enzyme encoded by the AGPAT2 gene in humans. The gene is located on chromosome 9q34.3 and the protein is associated with the endoplasmic reticulum membrane. AGPAT2 is part of the glycerol-3-phosphate acyltransferase (AGPAT) family, which catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triglycerides and phospholipids. The enzyme is relatively enriched in adipose tissue and liver, where it contributes to adipocyte development and lipid storage.

Functionally, AGPAT2 participates in the de novo synthesis pathway for glycerolipids, supplying phosphatidic acid for the production of triglycerides and phospholipids. Proper function of this enzyme is important for the formation and maintenance of adipose tissue, and disruptions can affect lipid handling and energy storage in cells.

Clinical significance of AGPAT2 mutations is most prominently observed in congenital generalized lipodystrophy type 1 (CGL1). This disorder is inherited in an autosomal recessive manner and results from loss-of-function variants in AGPAT2. Individuals with CGL1 have near-complete or partial absence of adipose tissue from birth or early life, with fat redistributed to liver and muscle. Associated metabolic complications include severe insulin resistance, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans. Diagnosis relies on molecular genetic testing confirming biallelic pathogenic variants in AGPAT2. Management is multidisciplinary, addressing metabolic risks; leptin replacement therapy has shown benefits for generalized lipodystrophy in some settings, alongside standard lifestyle and metabolic therapies. Mouse models of AGPAT2 deficiency mirror the human lipodystrophy phenotype and support the gene’s role in adipose tissue development and lipid metabolism.