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. 2021 Jan 22;12(2):148.
doi: 10.3390/genes12020148.

Functional Haplotype of LIPC Induces Triglyceride-Mediated Suppression of HDL-C Levels According to Genome-Wide Association Studies

Yu-Huang Liao  1 , Leay-Kiaw Er  1   2 , Semon Wu  3 , Yu-Lin Ko  2   4   5 , Ming-Sheng Teng  4
Affiliations

Functional Haplotype of LIPC Induces Triglyceride-Mediated Suppression of HDL-C Levels According to Genome-Wide Association Studies

Yu-Huang Liao et al. Genes (Basel). .

Abstract

Hepatic lipase (encoded by LIPC) is a glycoprotein in the triacylglycerol lipase family and mainly synthesized in and secreted from the liver. Previous studies demonstrated that hepatic lipase is crucial for reverse cholesterol transport and modulating metabolism and the plasma levels of several lipoproteins. This study was conducted to investigate the suppression effect of high-density lipoprotein cholesterol (HDL-C) levels in a genome-wide association study and explore the possible mechanisms linking triglyceride (TG) to LIPC variants and HDL-C. Genome-wide association data for TG and HDL-C were available for 4657 Taiwan-biobank participants. The prevalence of haplotypes in the LIPC promoter region and their effects were calculated. The cloned constructs of the haplotypes were expressed transiently in HepG2 cells and evaluated in a luciferase reporter assay. Genome-wide association analysis revealed that HDL-C was significantly associated with variations in LIPC after adjusting for TG. Three haplotypes (H1: TCG, H2: CTA and H3: CCA) in LIPC were identified. H2: CTA was significantly associated with HDL-C levels and H1: TCG suppressed HDL-C levels when a third factor, TG, was included in mediation analysis. The luciferase reporter assay further showed that the H2: CTA haplotype significantly inhibited luciferase activity compared with the H1: TCG haplotype. In conclusion, we identified a suppressive role for TG in the genome-wide association between LIPC and HDL-C. A functional haplotype of hepatic lipase may reduce HDL-C levels and is suppressed by TG.

Keywords: genome-wide association study; hepatic lipase; high-density lipoprotein cholesterol; suppression effect; triglyceride.

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Conflict of interest statement

The authors declare no conflict of interest and the funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results.

Figures

Figure 1
Figure 1
Genome-wide association studies (GWAS) analysis of high-density lipoprotein cholesterol (HDL-C) levels and LIPC variants. (A) Manhattan plot; (B) Manhattan plot after adjustment for TG; (C) Genetic region of rs261334 on chromosome 15.
Figure 1
Figure 1
Genome-wide association studies (GWAS) analysis of high-density lipoprotein cholesterol (HDL-C) levels and LIPC variants. (A) Manhattan plot; (B) Manhattan plot after adjustment for TG; (C) Genetic region of rs261334 on chromosome 15.
Figure 2
Figure 2
Luciferase reporter assay of pGL4.10-CCA, CTA and TCG in HepG2 cells. Activity of LIPC haplotype H2: CTA significantly decreased 30% and 26.3% as compared with H1: TCG and H3: CCA, respectively. Data were normalized to renilla activity and expressed as percentage of PGL 4.10.
See this image and copyright information in PMC

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