Navigating New Frontiers in Lipase Regulation

Endothelial lipase (EL; LIPG) is a phospholipase in a subfamily of lipid‑hydrolyzing enzymes that regulate lipid and lipoprotein metabolism. This family includes lipoprotein lipase (LPL, LPL), hepatic lipase (HL; LIPC), and pancreatic lipase (PL; PNLIP). EL directs the metabolism and remodeling of anti‑atherogenic high‑density lipoprotein (HDL) and influences catabolism of pro‑atherogenic triglyceride‑rich lipoproteins (TRLs). HDL, often called the “good cholesterol,” reduces inflammation and oxidative stress and promotes cholesterol removal via reverse cholesterol transport (RCT). Despite EL’s links to metabolic syndrome through HDL remodeling, its enzymatic function and biochemical regulation remain understudied relative to other family members. Using an optimized mammalian expression and purification protocol, we isolated active EL and identified a persistent co‑purifying partner by liquid chromatography–tandem mass spectrometry (LC‑MS/MS) and Western blot as apolipoprotein J (ApoJ; CLU). ApoJ is an extracellular chaperone and an apolipoprotein primarily associated with HDL. Using phospholipase assays, ultracentrifugation solubility tests, peptide‑array mapping, targeted mutagenesis, and complementary approaches, we show that ApoJ selectively regulates EL’s solubility and activity. ApoJ binds to EL’s hydrophobic N‑terminal lid and C‑terminal tryptophan loop, protecting the enzyme from aggregation. EL and ApoJ co‑fractionate with ApoA1/HDL in size‑exclusion chromatography of mouse plasma, and lipid‑rich ApoJ enhances EL’s hydrolysis of a lipoprotein‑like emulsion (Intralipid). These results link a specific molecular chaperone to EL‑mediated HDL remodeling. Because excessive EL activity depletes HDL surface phospholipids and impairs cholesterol‑efflux and anti‑inflammatory functions, ApoJ‑dependent stabilization of EL has clear relevance to systemic lipid disorders and cardiovascular risk. Moreover, given ApoJ’s genetic association with Alzheimer’s disease (AD) and the growing recognition of AD as a systemic metabolic‑vascular disorder, the EL–ApoJ partnership suggests a mechanistic pathway connecting dysregulated peripheral lipid metabolism to neurodegenerative vulnerability. The EL–ApoJ interaction therefore represents a promising target for therapeutic strategies aimed at restoring protective HDL function in metabolic and neurological disease.