ANGPTL4 (Angiopoietin-Like Protein 4 Fasting Lipase Regulator)
ANGPTL4 (angiopoietin like 4; HGNC:16039, NCBI Gene ID 51129) is a human locus mapped to chromosome band 19p13.2 that encodes secreted adipokine/hepatokine Angiopoietin-like protein 4 (406 aa). ANGPTL4 acts in fasting-induced inhibition of adipose lipoprotein lipase (LPL) & lipid partitioning, together with ANGPTL3 Gene, ANGPTL8 Gene, and LPL (Lipoprotein Lipase Gene). Encodes the fasting-induced ANGPTL4 protein that inhibits adipose lipoprotein lipase to redirect fatty acids to oxidative tissues.
Approved Symbol
ANGPTL4
Chromosomal Locus
19p13.2
Encoded Product
Secreted adipokine/hepatokine Angiopoietin-like protein 4 (406 aa)
Primary Pathway
Fasting-induced inhibition of adipose lipoprotein lipase (LPL) & lipid partitioning
Genomic Organization & Cytogenetic Locus: 7-exon gene on chromosome 19p13.2 containing a canonical peroxisome proliferator response element (PPRE) in intron 3, encoding a 406-amino-acid glycoprotein with an N-terminal coiled-coil domain that unfolds LPL dimers and a C-terminal fibrinogen-like domain.
Cellular & Tissue Expression Profile: Robustly induced during fasting, cold exposure, and hypoxia in white and brown adipocytes, hepatocytes, skeletal muscle fibers, and cardiomyocytes under transcriptional control of PPARA, PPARD, PPARG, and HIF1A.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Acts locally within the subendothelial space and intracellularly within adipocytes during fasting to promote unfolding and proprotein convertase cleavage of lipoprotein lipase (LPL), suppressing triglyceride uptake into white adipose tissue so circulating VLDL triglycerides are spared for heart and skeletal muscle oxidation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Carriers of the low-frequency loss-of-function missense variant p.Glu40Lys (E40K) and truncating alleles exhibit 35% lower fasting plasma triglycerides, higher HDL-cholesterol, improved glucose tolerance, and a 20–50% lower risk of coronary artery disease.
Therapeutic & Clinical Pharmacology: Whereas whole-body monoclonal antibody blockade of ANGPTL4 caused mesenteric lymphadenitis in preclinical high-fat models, hepatocyte-selective GalNAc-siRNA and ASO knockdown of hepatic ANGPTL4 lowers plasma triglycerides without lymphatic toxicity.