Identification of a Gain-of-Function LIPC Variant as a Novel Cause of Familial Combined Hypocholesterolemia

Abstract

Background: Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3 , has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family. Methods: Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC -E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance–based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC -E97G overexpression. Results: Family members carrying the LIPC -E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC -E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC -E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC -E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver. Conclusions: We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3 , causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.

Gain-of-Function Variants in Lipid Genes Enhance Biological Insight and Point Toward Therapeutic Opportunities

“…Detailed variant-driven structure-function assessment of other key players in the lipase pathways (eg, apolipo- proteins, chaperones, inhibitors) will add to our understanding of the biology of these proteins and enhance our therapeutic arsenal. These interesting findings by Dijk et al 6 arose from the discovery of a private variant identified in a single family with an extreme lipid phenotype. Careful mechanistic study of this variant revealed LIPC-E97G as the first GoF variant in HL and demonstrates the power of "N of 1" discoveries in humans with extreme phenotypes.…”

“…These interesting findings by Dijk et al 6 arose from the discovery of a private variant identified in a single family with an extreme lipid phenotype. Careful mechanistic study of this variant revealed LIPC -E97G as the first GoF variant in HL and demonstrates the power of “N of 1” discoveries in humans with extreme phenotypes.…”

“…5 The example of PCSK9 demonstrates the immense biological insights derived from allelic series that include GoF variants, and the lipid field has been interested in the identification of GoF variants in other genes known to affect lipoprotein metabolism. In this issue of Circulation , Dijk and colleagues 6 report the first GoF variant in the LIPC gene which encodes the enzyme HL (hepatic lipase).…”

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7

“…LIPC not only remodels LDL and HDL but also enhances lipid and lipoprotein uptake [ 37 ]. Interestingly, LIPC gene mutation is the second most common cause of familial hypocholesterolemia, after only angiopoietin-like 3 (ANGPTL3) [ 38 ], suggesting that LIPC is a promising target for the diagnosis of familial hypocholesterolemia.…”

UpToDate®

“…A number of rare genetic variants cause low levels of low-density lipoprotein cholesterol (LDL-C) and are associated with a reduced risk of atherosclerotic cardiovascular disease (ASCVD). Recently, a novel gain-of-function genetic variant in hepatic lipase (called LIPC-E97G ) was identified in a family with combined hypocholesterolemia (low LDL-C, low high-density lipoprotein cholesterol, normal triglyceride and apolipoprotein B concentrations) 4. The index case developed ASCVD at age 61 despite having low LDL-C levels (40 mg/dL or 1 mmol/L); other affected family members did not have ASCVD.…”