Using next-generation sequencing, researchers have discovered a dominant, gain-of-function variant in LIPC that underlies the combined hypocholesterolaemia observed in four generations of a French family. Previously, only one gene (ANGPTL3) had been causally linked to this condition. Individuals carrying the E97G variant in hepatic triacylglycerol lipase (LIPC) had very low plasma levels of LDL cholesterol, HDL cholesterol, LDL particle numbers and phospholipids. The variant specifically increases the phospholipase activity of LIPC, promoting the catabolism of triglyceride-rich lipoproteins. “Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism,” conclude the investigators.

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