ANGPTL8 (Angiopoietin-Like Protein 8 / Refeeding Lipase Switch)
ANGPTL8 (angiopoietin like 8; HGNC:24933, NCBI Gene ID 55908) is a human locus mapped to chromosome band 19p13.2 that encodes atypical coiled-coil angiopoietin-like protein 8 (198 aa). ANGPTL8 acts in ANGPTL3/8 & ANGPTL4/8 complex formation governing postprandial triglyceride trafficking, together with ANGPTL3 Gene, ANGPTL4 Gene, and LPL (Lipoprotein Lipase Gene). Encodes the insulin-induced refeeding factor ANGPTL8 that complexes with ANGPTL3 and ANGPTL4 to direct postprandial lipid storage.
Approved Symbol
ANGPTL8
Chromosomal Locus
19p13.2
Encoded Product
Atypical coiled-coil angiopoietin-like protein 8 (198 aa)
Loss-of-function p.Arg59Trp & truncating variants lower LDL-C and triglycerides
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 4-exon gene nested inside intron 14 of DOCK6 on chromosome 19p13.2, encoding a 198-amino-acid atypical member of the angiopoietin-like family that retains the N-terminal coiled-coil lipase-binding domain but completely lacks the C-terminal fibrinogen-like domain.
Cellular & Tissue Expression Profile: Strictly regulated by nutritional status: nearly undetectable during fasting but rapidly induced >10-fold upon refeeding and hyperinsulinemia in hepatocytes and white/brown adipocytes via insulin-SREBP-1c and LXR signaling.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Orchestrates the physiological ANGPTL3-4-8 model of triglyceride partitioning: after a meal, secreted hepatic ANGPTL8 forms a 3:1 endocrine complex with ANGPTL3 that potently inhibits LPL in oxidative cardiac and skeletal muscle, while locally in adipose tissue ANGPTL8 forms a complex with ANGPTL4 that neutralizes ANGPTL4 inhibitory activity, thereby directing postprandial circulating triglycerides into adipose tissue for storage.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Human heterozygotes for the p.Arg59Trp (R59W) variant or rare protein-truncating alleles display significantly lower fasting and postprandial triglycerides, lower LDL-cholesterol, elevated HDL-cholesterol, and reduced coronary atherosclerosis risk.
Therapeutic & Clinical Pharmacology: Monoclonal antibodies and GalNAc-conjugated siRNAs selectively targeting the ANGPTL8 or ANGPTL3/8 complex are in clinical development for mixed dyslipidemia and hypertriglyceridemia.