Alternative titles; symbols
HGNC Approved Gene Symbol: LIPC
SNOMEDCT: 720940008;
Cytogenetic location: 15q21.3 Genomic coordinates (GRCh38): 15:58,431,991-58,569,844 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.3 | [High density lipoprotein cholesterol level QTL 12] | 612797 | 3 | |
| {Diabetes mellitus, noninsulin-dependent} | 125853 | Autosomal dominant | 3 | |
| Hepatic lipase deficiency | 614025 | Autosomal recessive | 3 |
LIPC, which is synthesized in liver, is secreted and bound to hepatocytes and hepatic endothelial surfaces via heparin sulfate proteoglycans (HSPGs). Active LIPC exists as a homodimer and has broad substrate specificity, catalyzing the hydrolysis of fatty acyl chains at the sn-1 position of phospholipids and of mono-, di-, and triacylglycerols associated with a variety of lipoproteins, including high density lipoprotein (HDL). LIPC may also facilitate binding and uptake of lipoproteins and selective uptake of cholesteryl esters from lipoproteins (summary by Brown et al., 2004).
Datta et al. (1988) identified 3 cDNA clones for human hepatic lipase. The cDNA-derived amino acid sequence predicts a protein of 476 amino acid residues, preceded by a 23-residue signal peptide. Martin et al. (1988) also determined the cDNA sequence of this enzyme, called by them hepatic triglyceride lipase.
Hepatic lipase, like lipoprotein lipase (LPL; 238600) and lecithin:cholesterol acyltransferase (LCAT; 606967), plays a major role in the regulation of plasma lipids (Cai et al., 1989). LPL and HL are bound to and act at the endothelial surfaces of extrahepatic and hepatic tissues, respectively. Rare deficiencies of all of these enzymes have been identified in man, and all are associated with pathologic levels of circulating lipoprotein particles. LPL and HL show considerable nucleotide and amino acid sequence homology, suggesting that they constitute a multigene family derived from a common ancestral gene.
Unlike human HL, which is mainly anchored to the cell surface via binding to HSPG, mouse Hl has a low affinity for HSPG and is largely blood borne. Brown et al. (2004) created a chimeric HL protein deficient in HSPG binding, which they designated HLmt, by replacing the C-terminal HSPG-binding region of human HL with the corresponding region of mouse Hl. Infection of mice with HLmt resulted in elevated plasma lipase activity and severe hypoalphalipoproteinemia. Expression of HLmt, but not wildtype HL, reduced plasma total cholesterol and phospholipid levels, predominantly by decreasing the amount of HDL. Plasma and hepatocyte-associated levels of apoA-I (107680), the major apolipoprotein constituent of HDL, were also reduced by HLmt expression, but at a later time point. Brown et al. (2004) concluded that release of HL from cell surfaces has a profound effect on circulating HDL levels.
To separate the lipolytic and ligand-binding functions of HL, Gonzalez-Navarro et al. (2004) developed transgenic mice expressing wildtype human HL or catalytically inactive human HL on an Hl-null and apoE (107741)-null background. Both wildtype HL and inactive HL reduced plasma cholesterol, non-HDL cholesterol, and apoB (107730) levels, but only wildtype HL decreased plasma HDL cholesterol and apoA-I levels. Wildtype HL, but not inactive HL, contributed to plasma HDL metabolism, but it also enhanced atherosclerosis. In contrast, inactive HL reduced aortic atherosclerosis and enhanced apoB lipoproteins by enhancing their catabolism via the LDL receptor-related protein-1 (LRP1; 107770) pathway.
Cai et al. (1989) found that the LIPC gene spans over 60 kb and contains 9 exons and 8 introns. Exon 1 encodes the signal peptide; exon 4 encodes a region that binds to the lipoprotein substrate; exon 5 encodes an evolutionarily highly conserved region of potential catalytic function; and exons 6 and 9 encode sequences rich in basic amino acids thought to be important in anchoring the enzyme to the endothelial surface by interacting with acidic domains of the surface glycosaminoglycans. The human lipoprotein lipase gene has an identical exon-intron organization and contains analogous structural domains. Ameis et al. (1990) reported that the hepatic lipase gene comprises 9 exons spanning about 35 kb. The catalytic site appeared to be encoded by exon 4.
Sparkes et al. (1987) used a cDNA probe for HL, in Southern blot analysis of genomic DNA from mouse-human somatic cell human hybrids and for in situ hybridization, to demonstrate that the HL gene resides in band 15q21. Since the LPL gene is in band 8p22, the results demonstrated that the rare instances of combined deficiencies of both enzymes cannot be produced by mutation at the structural loci. Using a cloned hepatic lipase cDNA as a hybridization probe, Datta et al. (1988) performed Southern blot analysis of a panel of 13 human-rodent somatic cell hybrids. Concordance analysis indicated that the LIPH gene is located on 15q. Analysis of hybrids containing different translocations of chromosome 15 localized the gene to 15q15-q22. Heinzmann et al. (1988) described 2 RFLPs. Stocks et al. (1989) described 2 RFLPs, for BglII and XmnI.
Gross (2011) mapped the LIPC gene to chromosome 15q21.3 based on an alignment of the LIPC sequence (GenBank BC132825) with the genomic sequence (GRCh37).
Davis et al. (1990) stated that the hepatic lipase gene in the mouse resides on chromosome 9.
Hepatic Lipase Deficiency
In 6 individuals with complete HL deficiency (614025) from 2 unrelated families, Hegele et al. (1991) identified a heterozygous mutation in the LIPC gene (T383M; 151670.0001) that was not found in 50 controls. Hegele et al. (1991) identified a second mutation in the LIPC gene (S267F; 151670.0002) in the 3 affected individuals from 1 of the families, and Ruel et al. (2003) identified a second mutation in LIPC (A174T; 151670.0006) in affected members of the other family.
In a Finnish man with HL deficiency, Knudsen et al. (1996) identified compound heterozygosity for 2 mutations in the LIPC gene, the previously identified T383M mutation and L334F (151670.0007). The mutations, which were identified by a combination of single-strand confirmation polymorphism analysis and whole-exome sequencing of the LIPC gene, segregated with the disorder in the family.
In an Arab man, born to consanguineous parents, with HL deficiency, Al Riyami et al. (2010) identified homozygosity for the L334F mutation in the LIPC gene.
HDL Cholesterol Levels
In a metaanalysis of 25 published reports, Isaacs et al. (2004) found an association between a promoter SNP in the LIPC gene (-514C-T; 151670.0003) and HDL cholesterol levels (HDLCQ12; 612797).
Grarup et al. (2008) analyzed the effect of a SNP in the LIPC gene (-250G-A; 151670.0004) on metabolic traits and the risk of type 2 diabetes (T2D; see 125853) and found an association with fasting serum HDL cholesterol but not with T2D.
Iijima et al. (2008) analyzed alphalipoprotein levels in 2 independent Japanese populations consisting of 2,970 and 1,638 individuals, respectively, and found significant association between hyperalphalipoproteinemia (elevated HDL cholesterol) and a 2-SNP TA haplotype in intron 1 of the LIPC gene (151670.0005) in both populations (p = 0.00011 and 0.00070, respectively). The authors concluded that variation at the LIPC locus influences HDL metabolism.
In 6 individuals with complete HL deficiency (614025) from 2 unrelated families, 1 of French descent living in Quebec and a second of Irish and English descent living in Ontario, Hegele et al. (1991) found a 1221C-T transition in exon 8 of the LIPC gene that caused a thr383-to-met (T383M) substitution in the mature enzyme.
Hegele et al. (1991) identified a second mutation in the LIPC gene (S267F; 151670.0002) in the 3 affected individuals of the Ontario family, and Ruel et al. (2003) identified a second mutation in LIPC (A174T; 151670.0006) in affected members of the Quebec family.
In a Finnish man with HL deficiency, Knudsen et al. (1996) identified compound heterozygous mutations in the LIPC gene: T383M and a leu334-to-phe (L334F; 151670.0007) substitution in exon 7. The mutations, which were found by a combination of single-strand confirmation polymorphism analysis and whole-exome sequencing of the LIPC gene, segregated with the disorder in the family. The L334F mutation was identified in 8 of 170 alleles tested in the Finnish population. Transfection experiments in COS-1 cells showed that the T383M mutation resulted in reduced hepatic lipase expression and function, and that the L334F mutation resulted in normal hepatic lipase expression but reduced enzymatic function.
In the 3 individuals with complete HL deficiency (614025) from the Ontario family previously studied by Hegele et al. (1991) and found to have the T383M mutation in the LIPC gene (151670.0001), Hegele et al. (1991) identified a second mutation in the LIPC gene: an 873C-T transition in exon 8, resulting in a ser267-to-phe (S267F) substitution. Simple S267 heterozygotes had significantly depressed HL activity compared to genotypically normal family members. The S267F mutation was not found in members of the previously studied family from Quebec or in 72 controls.
To examine the relationship of a -514C-T single-nucleotide polymorphism (SNP) in the promoter region of the LIPC gene with total cholesterol, LDL and HDL cholesterol, triglycerides, and HL activity, Isaacs et al. (2004) performed a metaanalysis comprising 25 publications incorporating 24,000 individuals. Significant decreases were observed in HL activity for both the CT and TT genotypes compared with the CC genotype. Moreover, significant increases in HDL were found; the CT to CC comparison showed an increase in weighted mean difference (WMD) of 0.04 mmol/liter, and the increase in the TT versus CC difference was a WMD of 0.09 mmol/liter. These changes appeared to be stepwise, implying an allele dosage effect. All P values for these associations were less than 0.001. The authors concluded that their metaanalysis showed a positive association between the -514C-T polymorphism and HDL levels and a negative association between genotype and HL activity. These associations were largely unaffected by gender, ethnicity, or risk category.
Todorova et al. (2004) genotyped 490 subjects participating in the Finnish Diabetes Prevention Study at position -250 of the LIPC gene to investigate whether the -250G-A polymorphism of the LIPC gene predicts the conversion from impaired glucose tolerance to type II diabetes (125853). In the entire study population, the conversion rate to type II diabetes was 17.8% among subjects with -250G-G genotype and 10.7% among subjects with the -250A allele (P = 0.032). In multivariate logistic regression analysis, the -250G-G genotype predicted the conversion to diabetes independently of the study group (control or intervention), gender, weight, waist circumference at baseline, and change in weight and waist circumference. The authors concluded that the -250G-G genotype of the LIPC gene is a risk factor for type II diabetes. Therefore, genes regulating lipid and lipoprotein metabolism may be potential candidate genes for type II diabetes.
To investigate the effect of the -250G-A variant of LIPC (rs2070895) on metabolic traits and risk of type 2 diabetes, Grarup et al. (2008) genotyped this variant in 16,156 Danish subjects. They found an association of the A allele with a 0.057 mmol/l (95% CI 0.039-0.075) increase in fasting serum HDL cholesterol (P = 8 x 10(-10)) in 5,585 middle-aged treatment-naive subjects from a randomized population-based study. This association was replicated in 8,407 high-risk individuals. Carriers of the A allele had an increased fasting serum total cholesterol in both of these studies. Grarup et al. (2008) also observed an interaction between the A genotype and self-reported physical activity on serum HDL cholesterol (P = 0.002). The authors observed no association with type 2 diabetes in a cross-sectional design in this study.
Iijima et al. (2008) measured plasma alphalipoprotein (HDL) levels (HDLCQ12; 612797) in 2,970 Japanese individuals and identified a haplotype defined by the T and A alleles of rs8023503 and rs12594375, 2 SNPs in almost complete linkage disequilibrium in intron 1 of the LIPC gene, that was significantly associated with hyperalphalipoproteinemia (p = 0.00011). The association was replicated in an independent Japanese population consisting of 1,638 individuals (p = 0.0007).
In individuals with complete HL deficiency (614025) from the Quebec family previously studied by Hegele et al. (1991) and found to have a T383M mutation in the LIPC gene (151670.0001), Ruel et al. (2003) identified a second mutation in the LIPC gene: a G-to-A transition in exon 5, resulting in an ala174-to-thr (A174T) substitution in a highly conserved region of the mature protein.
For discussion of the leu334-to-phe (L334F) mutation in the LIPC gene that was found in compound heterozygous state in a Finnish patient with hepatic lipase deficiency (614025) by Knudsen et al. (1996), see 151670.0001.
In an Arab patient, born to consanguineous parents, with HL deficiency, Al Riyami et al. (2010) identified homozygosity for the L334F mutation in the LIPC gene. The mutation was identified by DNA sequencing of genomic DNA. Postheparin plasma hepatic lipase activity in the patient was zero.
Al Riyami, N., Al-Ali, A. M., Al-Sarraf, A. J., Hill, J., Sachs-Barrable, K., Hegele, R., Wasan, K. M., Frohlich, J. Hepatic lipase deficiency in a Middle-Eastern-Arabic male. BMJ Case Rep. 2010: bcr1220092589, 2010. [PubMed: 22798447] [Full Text: https://doi.org/10.1136/bcr.12.2009.2589]
Ameis, D., Stahnke, G., Kobayashi, J., McLean, J., Lee, G., Buscher, M., Schotz, M. C., Will, H. Isolation and characterization of the human hepatic lipase gene. J. Biol. Chem. 265: 6552-6555, 1990. [PubMed: 2324091]
Brown, R. J., Gauthier, A., Parks, R. J., McPherson, R., Sparks, D. L., Schultz, J. R., Yao, Z. Severe hypoalphalipoproteinemia in mice expressing human hepatic lipase deficient in binding to heparan sulfate proteoglycan. J. Biol. Chem. 279: 42403-42409, 2004. [PubMed: 15292235] [Full Text: https://doi.org/10.1074/jbc.M407748200]
Cai, S.-J., Wong, D. M., Chen, S.-H., Chan, L. Structure of the human hepatic triglyceride lipase gene. Biochemistry 28: 8966-8971, 1989. [PubMed: 2605236] [Full Text: https://doi.org/10.1021/bi00449a002]
Datta, S., Luo, C.-C., Li, W.-H., VanTuinen, P., Ledbetter, D. H., Brown, M. A., Chen, S.-H., Liu, S., Chan, L. Human hepatic lipase: cloned cDNA sequence, restriction fragment length polymorphisms, chromosomal localization, and evolutionary relationships with lipoprotein lipase and pancreatic lipase. J. Biol. Chem. 263: 1107-1110, 1988. [PubMed: 2447084]
Davis, R. C., Ben-Zeev, O., Martin, D., Doolittle, M. H. Combined lipase deficiency in the mouse: evidence of impaired lipase processing and secretion. J. Biol. Chem. 265: 17960-17966, 1990. [PubMed: 2211673]
Gonzalez-Navarro, H., Nong, Z., Amar, M. J. A., Shamburek, R. D., Najib-Fruchart, J., Paigen, B. J., Brewer, H. B., Jr., Santamarina-Fojo, S. The ligand-binding function of hepatic lipase modulates the development of atherosclerosis in transgenic mice. J. Biol. Chem. 279: 45312-45321, 2004. [PubMed: 15304509] [Full Text: https://doi.org/10.1074/jbc.M406495200]
Grarup, N., Andreasen, C. H., Andersen, M. K., Albrechtsen, A., Sandbaek, A., Lauritzen, T., Borch-Johnsen, K., Jorgensen, T., Schmitz, O., Hansen, T., Pedersen, O. The -250G-A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects. J. Clin. Endocr. Metab. 93: 2294-2299, 2008. [PubMed: 18364377] [Full Text: https://doi.org/10.1210/jc.2007-2815]
Gross, M. B. Personal Communication. Baltimore, Md. 6/3/2011.
Hegele, R. A., Little, J. A., Connelly, P. W. Compound heterozygosity for mutant hepatic lipase in familial hepatic lipase deficiency. Biochem. Biophys. Res. Commun. 179: 78-84, 1991. [PubMed: 1883393] [Full Text: https://doi.org/10.1016/0006-291x(91)91336-b]
Hegele, R. A., Vezina, C., Moorjani, S., Lupien, P. J., Gagne, C., Brun, L. D., Little, J. A., Connelly, P. W. A hepatic lipase gene mutation associated with heritable lipolytic deficiency. J. Clin. Endocr. Metab. 72: 730-732, 1991. [PubMed: 1671786] [Full Text: https://doi.org/10.1210/jcem-72-3-730]
Heinzmann, C., Ladias, J., Antonarakis, S., Diep, A., Schotz, M., Lusis, A. J. Two polymorphisms for the human hepatic lipase (HL) gene. Nucleic Acids Res. 16: 4739 only, 1988. [PubMed: 2454457] [Full Text: https://doi.org/10.1093/nar/16.10.4739]
Iijima, H., Emi, M., Wada, M., Daimon, M., Toriyama, S., Koyano, S., Sato, H., Hopkins, P. N., Hunt, S. C., Kubota, I., Kawata, S., Kato, T. Association of an intronic haplotype of the LIPC gene with hyperalphalipoproteinemia in two independent populations. J. Hum. Genet. 53: 193-200, 2008. [PubMed: 18160998] [Full Text: https://doi.org/10.1007/s10038-007-0236-0]
Isaacs, A., Sayed-Tabatabaei, F. A., Njajou, O. T., Witteman, J. C. M., van Duijn, C. M. The -514 C-T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis. J. Clin. Endocr. Metab. 89: 3858-3863, 2004. [PubMed: 15292318] [Full Text: https://doi.org/10.1210/jc.2004-0188]
Knudsen, P., Antikainen, M., Ehnholm, S., Uusi-Oukari, M., Tenkanen, H., Lahdenpera, S., Kahri, J., Tilly-Kiesi, M., Bensadoun, A., Taskinen, M.-J., Ehnholm, C. A compound heterozygote for hepatic lipase gene mutations leu334-to-phe and thr383-to-met: correlation between hepatic lipase activity and phenotypic expression. J. Lipid Res. 37: 825-834, 1996. [PubMed: 8732782]
Martin, G. A., Busch, S. J., Meredith, G. D., Cardin, A. D., Blankenship, D. T., Mao, S. J. T., Rechtin, A. E., Woods, C. W., Racke, M. M., Schafer, M. P., Fitzgerald, M. C., Burke, D. M., Flanagan, M. A., Jackson, R. L. Isolation and cDNA sequence of human postheparin plasma hepatic triglyceride lipase. J. Biol. Chem. 263: 10907-10914, 1988. [PubMed: 2839510]
Ruel, I. L., Couture, P., Gagne, C., Deshaies, Y., Simard, J., Hegele, R. A., Lamarche, B. Characterization of a novel mutation causing hepatic lipase deficiency among French Canadians. J. Lipid Res. 44: 1508-1514, 2003. [PubMed: 12777476] [Full Text: https://doi.org/10.1194/jlr.M200479-JLR200]
Sparkes, R. S., Zollman, S., Klisak, I., Kirchgessner, T. G., Komaromy, M. C., Mohandas, T., Schotz, M. C., Lusis, A. J. Human genes involved in lipolysis of plasma lipoproteins: mapping of loci for lipoprotein lipase to 8p22 and hepatic lipase to 15q21. Genomics 1: 138-144, 1987. [PubMed: 3692485] [Full Text: https://doi.org/10.1016/0888-7543(87)90005-x]
Stocks, J., Li, S. R., Thorn, J., Chan, L., Galton, D. J. Three RFLPs at the human hepatic lipase locus. (Abstract) Cytogenet. Cell Genet. 55: 1086 only, 1989.
Todorova, B., Kubaszek, A., Pihlajamaki, J., Lindstrom, J., Eriksson, J., Valle, T. T., Hamalainen, H., Ilanne-Parikka, P., Keinanen-Kiukaanniemi, S., Tuomilehto, J., Uusitupa, M., Laakso, M. The G-250A promoter polymorphism of the hepatic lipase gene predicts the conversion from impaired glucose tolerance to type 2 diabetes mellitus: the Finnish Diabetes Prevention Study. J. Clin. Endocr. Metab. 89: 2019-2023, 2004. [PubMed: 15126514] [Full Text: https://doi.org/10.1210/jc.2003-031325]