Identification of a gain-of-function LIPC variant as a novel cause of familial combined hypocholesterolemia

Background and Aims : Atherosclerotic cardiovascular disease is the main cause of mortality worldwide strongly influenced by plasma low-density lipoprotein cholesterol (LDL-C) levels. So far, only few genes with a strong causal relationship to LDL-C levels have been identified. Here, we aimed elucidate genetic origin an unexplained combined hypocholesterolemia inherited in four generations French family.Methods: Using new generation sequencing, identified novel dominant rare variant LIPC gene, which encodes for hepatic lipase (HL), that co-segregates phenotype.Results: Nuclear magnetic resonance lipidomics analysis revealed family members carrying LIPC-E97G had extremely low LDL-C, high-density (HDL-C), LDL particle numbers phospholipids. The lysoPL/PL ratio was increased carriers, suggestive lipolytic activity on In vitro vivo studies confirmed specifically increases phospholipase HL without altering TG activity. Finally, APOE3-CETP Leiden mice overexpressing recapitulated hypocholesterolemic phenotype demonstrated promotes catabolism triglyceride-rich lipoproteins peripheral tissues, but not liver.Conclusions: summary, as second gene causally involved familial hypocholesterolemia. Our mechanistic data highlight critical role homeostasis suggest clearance mechanism. family. Methods: phenotype. Results: liver. Conclusions: