LIPC – Hyperlipidemia due to hepatic triglyceride lipase deficiency

Autosomal recessive hyperlipidemia due to hepatic triglyceride lipase deficiency is caused by biallelic loss-of-function variants in LIPC, leading to markedly reduced or absent hepatic lipase activity and consequent elevation of plasma triglycerides and cholesterol. The mode of inheritance is autosomal recessive, with obligate heterozygotes showing intermediate enzyme activity but usually subclinical lipid elevations. Multiple unrelated families and individuals with biallelic LIPC variants have been reported, with segregation of enzyme deficiency and hyperlipidemia in pedigrees and concordant in vitro functional data demonstrating impaired lipolytic activity.

Genetic evidence includes the original large family with a homozygous LIPC defect presenting with hypertriglyceridemia and chylomicronemia, where two half-sisters were similarly affected and obligate heterozygotes had intermediate enzyme levels ([PMID:1968704]). In a separate retrospective chart review of 46 heterozygous carriers of pathogenic LIPC variants, rare LoF alleles (e.g., c.517G>A (p.Val173Met)) were associated with significantly elevated total cholesterol, LDL-C, and triglycerides compared to controls, suggesting semi-dominant effects ([PMID:39518997]).

Functional assays support haploinsufficiency and loss of catalytic function: promoter variants such as -514C>T reduce transcription by 45% in HepG2 reporter assays ([PMID:11257263]), while missense mutations including c.517G>A (p.Val173Met) confer only 46% of wild-type lipase activity in transfected cells ([PMID:23219720]). Furthermore, novel missense and frameshift mutations identified in Thai and Thai–Chinese cohorts show diminished enzyme secretion and activity, consistent with pathogenicity ([PMID:19428034]).

No robust conflicting evidence has been reported disputing LIPC’s role in hepatic lipase deficiency, although heterozygous carrier phenotypes vary with background genetics and environment. Overall, the genetic and functional data converge on a loss-of-function mechanism leading to autosomal recessive hyperlipidemia.

Key Take-home: Biallelic LIPC loss-of-function variants cause autosomal recessive hepatic lipase deficiency with elevated triglycerides and cholesterol, and heterozygous carriers exhibit intermediate lipid elevations, supporting its clinical utility in genetic diagnosis and risk stratification.

References

• American journal of human genetics • 1990 • Coexistence of abnormalities of hepatic lipase and lipoprotein lipase in a large family PMID:1968704
• International journal of molecular sciences • 2024 • Phenotype in Individuals with Heterozygous Rare Variants in LIPC Encoding Hepatic Lipase. PMID:39518997
• Atherosclerosis • 2001 • Hepatic lipase promoter activity is reduced by the C-480T and G-216A substitutions present in the common LIPC gene variant, and is increased by Upstream Stimulatory Factor. PMID:11257263
• Clinica chimica acta; international journal of clinical chemistry • 2013 • Functional characterization of novel variants in the CETP promoter and the LIPC gene in subjects with hyperalphalipoproteinemia. PMID:23219720
• Metabolism: clinical and experimental • 2009 • Two novel mutations and functional analyses of the CETP and LIPC genes underlying severe hyperalphalipoproteinemia. PMID:19428034

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