APOA5 (apolipoprotein A5; HGNC:17288, NCBI Gene ID 116519) is a human locus mapped to chromosome band 11q23.3 that encodes secreted apolipoprotein A-V hydrophobic apolipoprotein (343 mature aa). APOA5 acts in suppression of ANGPTL3/8 complex & acceleration of LPL-mediated triglyceride lipolysis, together with LPL (Lipoprotein Lipase Gene), ANGPTL3 Gene, and ANGPTL8 Gene. Encodes apolipoprotein A-V, an activator of intravascular triglyceride lipolysis that suppresses the ANGPTL3/8 inhibitor complex.
Suppression of ANGPTL3/8 complex & acceleration of LPL-mediated triglyceride lipolysis
Clinical / Therapeutic Role
LoF mutations cause severe hypertriglyceridemia (HTG) & elevated myocardial infarction risk
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 4-exon gene identified by comparative human-mouse genomic sequencing in 2001 at the telomeric end of the APOA1-APOC3-APOA4-APOA5 cluster on chromosome 11q23.3, containing a functional PPAR-alpha response element (PPRE) in its proximal promoter.
Cellular & Tissue Expression Profile: Expressed exclusively in hepatic hepatocytes, circulating in human plasma at very low molar concentrations (~150–400 ng/mL, roughly 1,000-fold lower than ApoA-I or ApoC-III) distributed across VLDL, chylomicrons, and HDL.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Despite its trace plasma concentration, ApoA-V potently lowers plasma triglycerides by binding selectively to the ANGPTL3/8 complex—inactivating ANGPTL3/8-mediated inhibition of lipoprotein lipase (LPL)—and by tethering triglyceride-rich lipoproteins to endothelial glycosaminoglycans-GPIHBP1-LPL complexes.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Rare loss-of-function nonsense or missense mutations (such as p.Gln148Ter and p.Gly185Cys) cause autosomal recessive or codominant severe hypertriglyceridemia and chylomicronemia, and exome sequencing demonstrates that heterozygous APOA5 loss-of-function carriers have a 2.2-fold increased risk of early-onset myocardial infarction.
Therapeutic & Clinical Pharmacology: Up-regulated transcriptionally by PPAR-alpha agonists (pemafibrate, fenofibrate), while recombinant engineered ApoA-V biologics and ANGPTL3/8-neutralizing antibodies mimic its physiological mechanism.