Common C-to-T Substitution at Position −480 of the Hepatic Lipase Promoter Associated With a Lowered Lipase Activity in Coronary Artery Disease Patients

Jansen, Hans; Verhoeven, Adrie J.M.; Weeks, Lloyd E.; Kastelein, J.J.P.; Halley, D. J. J.; Ouweland, A. Van Den; Jukema, J. Wouter; Seidell, Jacob C.; Birkenhäger, J. C.

doi:10.1161/01.atv.17.11.2837

Cited by 146 publications

(195 citation statements)

References 40 publications

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“…Also, the polymorphism influences HDL subclass distribution, with higher HDL2b and lower HDL3a Couture et al 2000). Consistently, the Ϫ514T allele, also denoted as Ϫ480T by others, has shown an association with the elevated HDL-C levels in Europeans (Murtomaki et al 1997;Jansen et al 1997), Finns (Tahvanainen et al 1998), and Americans (Zambon et al 1998;Couture et al 2000).…”

Section: Introductionsupporting

confidence: 55%

Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population

et al. 2001

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Genetic factors may play a major role in determining serum high-density lipoprotein (HDL) cholesterol (HDL-C) levels in the general population. Cholesteryl ester transfer protein (CETP) is a strong genetic factor as a determinant of HDL-C levels in Japanese, whereas hepatic lipase (HL) plays a predominant role in Caucasian populations. We investigated the effects of HL gene promoter polymorphisms on HDL-C levels in a general population of Japanese men (n ϭ 299). An HL promoter polymorphism of Ϫ514C/T explained a considerable variance of HDL-C (2.9%), as compared with CETP mutations of D442G and IVS14 ϩ 1G Ͼ A (3.6% and 1.9%). HL promoter variation of the Ϫ514C/C genotype, reported to have high HL activity, had significant effects on decreasing HDL-C levels (Ϫ3.8 mg/dl), but Ϫ514T allele carriers had a weak effect on increasing HDL-C levels. The frequency of the Ϫ514T allele was three times higher (0.50) in the Japanese than in Caucasian populations (0.15-0.19). Thus, the higher frequency of the HL Ϫ514T allele, along with CETP gene mutations, could explain about 9% of phenotypic variability of HDL-C. These genetic attributes may be among the many factors that contribute to the relatively higher serum HDL-C levels in Japanese subjects.

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Section: Introductionsupporting

confidence: 55%

Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population

et al. 2001

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“…27 Several groups have also shown that the LIPC promoter polymorphisms, all in linkage disequilibrium in whites, are associated with HL activity. 28,29,53,54 Our data show that the LIPC promoter polymorphism influences the relationship between IAF and HL activity. The difference in HL activity between the 2 genotypes is most evident when 2 curves diverge at relatively high levels of IAF (Figure 2).…”

Section: Discussionmentioning

confidence: 62%

“…53 As seen in Table 2, insulin levels are marginally related to HL activity, but this effect is not seen after adjustment for IAF. In multivariate analysis, insulin added no further significance above IAF in predicting hepatic lipase.…”

Section: Carr Et Al Regulation Of Hl Activitymentioning

confidence: 84%

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A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women

Carr

Hokanson

Deeb

et al. 1999

ATVB

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Abstract-High hepatic lipase (HL) activity is associated with an atherogenic lipoprotein profile of small, dense LDL particles and lower HDL 2 -C. Intra-abdominal fat (IAF) is positively associated with HL activity. A hepatic lipase gene (LIPC) promoter variant (G3 A Ϫ250 ) is associated with lower HL activity, higher HDL 2 -C, and less dense LDL particles.To determine whether the LIPC promoter polymorphism acts independently of IAF to regulate HL, 57 healthy, premenopausal women were studied. The LIPC promoter A allele was associated with significantly lower HL activity (GA/AAϭ104Ϯ34 versus GGϭ145Ϯ57 nmoles ⅐ mL Ϫ1 ⅐ min Ϫ1 , Pϭ0.009 lipolytic enzyme that is a serine hydrolase. It appears to act not only in hydrolysis of triglyceride (TG) and phospholipid in HDL and LDL 1,2 but also as a ligand directing lipoproteins to hepatic cell surface receptors. 3-5 HL is secreted by hepatocytes and anchored to the liver sinusoidal surface by heparin sulfate proteoglycans. 6 The HL gene (LIPC) spans 35 kb of DNA, maps to chromosome 15q21, and is composed of nine exons and eight introns. 7,8 HL plays a role in the metabolic processing of both HDL and LDL. HL acts to convert large, buoyant HDL 2 to small, dense HDL 3 by modulating the phospholipid content of the particle. 9,10 By functioning as a ligand between the lipoprotein and cell surface receptors, HL has been shown to play a role in increased clearance of HDL particles 11,12 and remnant lipoproteins. 13 HL also catalyzes the hydrolysis of triglyceride and phospholipid in large, buoyant LDL forming small, dense more atherogenic LDL particles. 14 Increased risk of premature coronary artery disease (CAD) has been shown to be associated with the presence of small, dense LDL particles. [15][16][17][18][19] Similarly, low HDL-C is another major risk factor for CAD. 20,21 It appears that gender differences in HDL-C levels may account, in part, for the temporal separation in CAD risk between men and women. 20 HDL-C metabolism is modulated by both environmental and genetic factors that combine to account for the significant interindividual variation in HDL-C levels and hence CAD risk. Sedentary lifestyle, 22 tobacco usage, 23 and obesity 24 are all associated with lower HDL-C levels. Forty to sixty percent of the variation in HDL levels appear to be genetic, 25 and Cohen et al have demonstrated genetic linkage between the hepatic lipase promoter (LIPC) locus and HDL-C levels that account for approximately 25% of the interindividual variation in plasma HDL-C levels. 26 HL activity appears to be influenced by several different factors including intra-abdominal fat (IAF), 27 ethnic background, 28,29 sex-steroid hormones, 30 -32 and LIPC genotype. 28,29 Four polymorphisms have now been identified in the 5Ј flanking region of the LIPC gene; a G to A substitution at position Ϫ250, C to T at Ϫ514, T to C at Ϫ710, and A to G at Ϫ763, which appear to be in complete linkage disequilibrium in white populations. 33 The allele frequency of the substitution ranges from 0.15 33 to 0.21 29 ...

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“…Instead, acute hyperinsulinaemia actually reduces HL expression [14]. HL activity correlates with parameters of insulin resistance in non-diabetic men [15,16] and in FCHL [16]. In an animal model, HL levels were increased upon induction of insulin resistance, which could be partially reversed by treatment with an insulin sensitiser [17].…”

Section: Introductionmentioning

confidence: 97%

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

Deursen¹,

Jansen²,

Verhoeven³

2008

Diabetologia

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Aims/hypothesis Elevated hepatic lipase (HL, also known as LIPC) expression is a key factor in the development of the atherogenic lipid profile in type 2 diabetes and insulin resistance. Recently, genetic screens revealed a possible association of type 2 diabetes and familial combined hyperlipidaemia with the USF1 gene. Therefore, we investigated the role of upstream stimulatory factors (USFs) in the regulation of HL. Methods Levels of USF1, USF2 and HL were measured in HepG2 cells cultured in normal-or high-glucose medium (4.5 and 22.5 mmol/l, respectively) and in livers of streptozotocin-treated rats.Results Nuclear extracts of cells cultured in high glucose contained 2.5±0.5-fold more USF1 and 1.4±0.2-fold more USF2 protein than cells cultured in normal glucose (mean± SD, n=3). This coincided with higher DNA binding of nuclear proteins to the USF consensus DNA binding site. Secretion of HL (2.9±0.5-fold), abundance of HL mRNA (1.5±0.2-fold) and HL (-685/+13) promoter activity (1.8± 0.3-fold) increased in parallel. In chromatin immunoprecipitation assays, the proximal HL promoter region was immunoprecipitated with anti-USF1 and anti-USF2 antibodies. Co-transfection with USF1 or USF2 cDNA stimulated HL promoter activity 6-to 16-fold. USF and glucose responsiveness were significantly reduced by removal of the −310E-box from the HL promoter. Silencing of the USF1 gene by RNA interference reduced glucose responsiveness of the HL (−685/+13) promoter region by 50%. The hyperglycaemia in streptozotocin-treated rats was associated with similar increases in USF abundance in rat liver nuclei, but not with increased binding of USF to the rat Hl promoter region. Conclusions/interpretation Glucose increases HL expression in HepG2 cells via elevation of USF1 and USF2. This mechanism may contribute to the development of the dyslipidaemia that is typical of type 2 diabetes.

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Common C-to-T Substitution at Position −480 of the Hepatic Lipase Promoter Associated With a Lowered Lipase Activity in Coronary Artery Disease Patients

Cited by 146 publications

References 40 publications

Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population

Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population

A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

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