LPL (lipoprotein lipase; HGNC:6677, NCBI Gene ID 4023) is a human locus mapped to chromosome band 8p21.3 that encodes endothelial-anchored lipoprotein lipase (475 aa; EC 3.1.1.34). LPL acts in hydrolysis of chylomicron & VLDL core triglycerides at capillary endothelium, together with APOC3 (Apolipoprotein C-III Inhibitor Gene), APOA5 (Apolipoprotein A-V Activator Gene), and ANGPTL3 Gene. Encodes lipoprotein lipase, the rate-limiting intravascular enzyme hydrolyzing triglycerides in chylomicrons and VLDL.
Genomic Organization & Cytogenetic Locus: 10-exon gene on chromosome 8p21.3 encoding a 475-amino-acid secreted glycoprotein (448 mature residues) containing an N-terminal alpha/beta-hydrolase catalytic triad (Ser159-Asp183-His268) covered by an amphipathic lid and a C-terminal PLAT domain that binds lipoproteins and GPIHBP1.
Cellular & Tissue Expression Profile: Synthesized by parenchymal white and brown adipocytes, cardiac myocytes, and oxidative skeletal muscle fibers, then transcytosed across capillary endothelial cells by glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) to project into the vascular lumen.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Requires apolipoprotein C-II (APOC2) as an obligate cofactor and ApoA-V (APOA5) as a stabilizer to hydrolyze triacylglycerols within circulating chylomicrons and VLDL particles into 2-monoacylglycerol and non-esterified fatty acids for tissue beta-oxidation or re-esterification, while being negatively regulated by APOC3, ANGPTL3, ANGPTL4, and ANGPTL8.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations cause classic type I hyperlipoproteinemia (familial chylomicronemia syndrome, FCS), presenting with milky lipemic plasma, fasting triglycerides >1,000–2,000 mg/dL, eruptive xanthomas, lipemia retinalis, and life-threatening acute pancreatitis; conversely, the common gain-of-function truncation variant p.Ser447Ter (S447X) lowers triglycerides and protects against coronary artery disease.
Therapeutic & Clinical Pharmacology: LPL p.Ser447Ter delivered via AAV1 (alipogene tiparvovec / Glybera) was the first gene therapy approved in Europe (2012); today intravascular LPL activity is clinically enhanced by targeting its endogenous inhibitors APOC3 (olezarsen, plozasiran) and ANGPTL3 (evinacumab, zodasiran).