Lipoprotein lipase (LPL) is a critical enzyme catalyzing triglyceride hydrolysis from circulating chylomicrons and VLDL, thereby controlling fatty acid delivery to tissues for oxidation and storage 1. LPL functions as the primary 'gatekeeper' regulating fatty acid uptake into tissues 1. The enzyme is recruited to vascular endothelium via binding to GPIHBP1 and heparan sulfate proteoglycans, where it mediates triglyceride-rich lipoprotein margination in capillaries 2. LPL activity is tightly regulated by extracellular proteins including ANGPTL3/4/8, which inhibit its function; conversely, APOA5 suppresses ANGPTL3/8 inhibitory activity, thereby enhancing LPL-mediated triglyceride clearance 3. Fasting decreases adipose tissue LPL activity through ANGPTL4 induction via cortisol and fatty acids while decreasing insulin 4. Clinically, LPL dysfunction causes hyperlipoproteinemia type I and familial combined hyperlipidemia characterized by severe hypertriglyceridemia and acute pancreatitis risk 2. Emerging evidence indicates LPL participates in NAFLD progression to hepatocellular carcinoma through the LPL/FABP4/CPT1 metabolic axis 5. Additionally, LPL acts as a tumor suppressor in prostate cancer, with biallelic inactivation occurring through chr8 deletion and promoter hypermethylation 6. LPL genetic variants affecting remnant cholesterol metabolism are targets for novel therapeutics addressing residual atherosclerotic cardiovascular disease risk 7.