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Jonathan Cohen - One of the best experts on this subject based on the ideXlab platform.
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Hepatic Lipase lipc promoter polymorphism in men with coronary artery disease allele frequency and effects on Hepatic Lipase activity and plasma hdl c concentrations
Arteriosclerosis Thrombosis and Vascular Biology, 1999Co-Authors: Ralph V Shohet, Scott M Grundy, Gloria L Vega, Azam Anwar, Joaquin E Cigarroa, Jonathan CohenAbstract:Hepatic Lipase is an important determinant of plasma HDL concentration and LDL subclass distribution and may therefore influence susceptibility to coronary artery disease (CAD). To assess the effect of genetic variation in Hepatic Lipase activity on CAD susceptibility, we determined the frequency of the -514T allele of Hepatic Lipase in white men with CAD and in controls who did not have CAD. In men with CAD, postheparin plasma Hepatic Lipase activity was 15% to 20% lower in heterozygotes and 30% lower in homozygotes for the -514T allele. Allele frequencies were similar in cases and controls, however, and were consistent with Hardy-Weinberg expectation in both groups. This finding was confirmed in a second group comprising cases with premature symptomatic CAD and controls who were free of disease. These data indicate that a primary decrease in Hepatic Lipase activity of as much as 30% does not influence susceptibility to CAD in white men.
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Hepatic Lipase new insights from genetic and metabolic studies
Current Opinion in Lipidology, 1999Co-Authors: Jonathan Cohen, Gloria Lena Vega, Scott M GrundyAbstract:Hepatic Lipase catalyses the hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Genetic deficiency of this enzyme is associated with a unique plasma lipoprotein profile, characterized by hypertriglyceridemia and elevated concentrations of intermediate density lipopro
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Hepatic Lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men genetic and pharmacological evidence
Journal of Lipid Research, 1999Co-Authors: Scott M Grundy, Gloria Lena Vega, James D Otvos, David L Rainwater, Jonathan CohenAbstract:Several studies have reported an inverse relation- ship between Hepatic Lipase activity and plasma high density lipoprotein (HDL) cholesterol concentrations. The purpose of the present study was to determine whether genetic and pharmacological variation in Hepatic Lipase activity alters the distribution of HDL subclasses. Two independent ana- lytical methods (nuclear magnetic resonance and gradient gel electrophoresis) were used to compare HDL subclass distributions in 11 homozygotes for the 2 514C allele of he- patic Lipase and in 6 homozygotes for the 2 514T allele. Mean Hepatic Lipase activity was 45 6 15 mmol ? l 2 1 ? hr 2 1 in 2 514C homozygotes and 20 6 7 mmol ? l 2 1 ? hr 2 1 in 2 514T homozygotes. Both analytical methods indicated that HDL 2b was significantly higher and HDL 3a was significantly lower in 2 514T homozygotes than in 2 514C homozygotes. No dif- ferences were noted in the other HDL fractions (HDL 2a , HDL 3b , and HDL 3c ). To determine the effects of increased Hepatic Lipase activity, 20 men were given the synthetic ana- bolic steroid, stanozolol. Stanozolol treatment increased he- patic Lipase activity more than two-fold (38 6 18 to 85 6 25 mmol ? l 2 1 ? hr 2 1 ), and markedly reduced the plasma concen- trations of the larger HDL subclasses (HDL 2b and HDL 2a ).
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body mass index and Hepatic Lipase gene lipc polymorphism jointly influence postheparin plasma Hepatic Lipase activity
Journal of Lipid Research, 1998Co-Authors: Liangcai Nie, Jinping Wang, Luther T Clark, Aylmer Tang, Gloria Lena Vega, Scott M Grundy, Jonathan CohenAbstract:The -514 polymorphism in the Hepatic Lipase gene (LIPC) is associated with decreased Hepatic Lipase activity. In the present study, the interaction between body mass index (BMI), the -514 polymorphism, and Hepatic Lipase activity was examined in 118 white men and in 51 African American men. BMI was significantly positively correlated with Hepatic Lipase activity in both populations. BMI was similar in men with genetic differences in Hepatic Lipase activity, indicating that high Hepatic Lipase activity did not cause increased BMI. The data therefore suggest that high BMI leads to increased Hepatic Lipase activity. The actions of BMI and the -514 polymorphism on Hepatic Lipase activity appear to be additive and independent, rather than synergistic. This finding indicates that Hepatic Lipase activity is a multifactorial trait, determined in part by polymorphism within the LIPC gene as well as by factors that influence BMI.
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Hepatic Lipase activity is lower in African American men than in white American men: effects of 5' flanking polymorphism in the Hepatic Lipase gene (LIPC).
Journal of lipid research, 1998Co-Authors: Gloria Lena Vega, Luther T Clark, Aylmer Tang, Scott M Grundy, Santica M. Marcovina, Jonathan CohenAbstract:Plasma high density lipoprotein cholesterol (HDL-C) concentrations are higher in African American men than in white men, but the mechanism(s) responsible for this ethnic difference has not been elucidated. This study examined the relationship between Hepatic Lipase activity, plasma HDL-C concentrations, and a Hepatic Lipase polymorphism (-514T) in African American and white American men. Consistent with previous reports, plasma HDL-C concentrations were significantly higher in African American men than in white American men. Mean post-heparin plasma Hepatic Lipase activity was significantly lower in African American than in white American men (27 +/- 12 vs. 44 +/- 17 mmol x h(-1) x l(-1), P < 0.001). The -514T Hepatic Lipase allele was associated with low Hepatic Lipase activity in both populations, and was 3-fold more common among African Americans than white Americans. Taken together, these data suggest that genetic differences in Hepatic Lipase activity contribute to the differences in plasma HDL-C concentrations between African American men and white American men.
John D Brunzell - One of the best experts on this subject based on the ideXlab platform.
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ethnic differences in Hepatic Lipase and hdl in japanese black and white americans role of central obesity and lipc polymorphisms
Journal of Lipid Research, 2004Co-Authors: Molly C Carr, John D Brunzell, Samir S DeebAbstract:Hepatic Lipase activity (HLA) is a determinant of HDL levels, and a polymorphism in the Hepatic Lipase gene (LIPC) promoter (C-514T) has been hypothesized to account for higher HDL in blacks and Japanese compared with whites. To determine whether the polymorphism contributes to ethnic differences in HDL, we compared LIPC allele frequencies and HLA in Japanese American (JA; n = 84), black American (BA; n = 94), and white American (WA; n = 110) men and women. The LIPC polymorphism was associated with HLA in all cohorts (BA, P = 0.012; JA, P = 0.008; WA, P = 0.009). WA men had 49% and 58% higher HLA than BA and JA men, respectively (both P < 0.05), yet no differences in HLA were found between the women. The higher HLA in the WA men remained after adjustment for the LIPC polymorphism's effect on HLA (P = 0.037) but was erased after adjustment for waist-to-hip-ratio (P = 0.46). Although the WA men had lower HDL and HDL 3 than the JA and BA men (all P < 0.05 ), there were no differences in HDL 2 , implying that variance in HLA may not underlie the ethnic differences in HDL levels. These results suggest that 1) the LIPC promoter polymorphism contributes to variation in HLA and HDL 2 in the three ethnic groups; 2) WA men had higher HLA than BA and JA men, related to ethnic differences in central adiposity but not LIPC allele frequency; and 3) the higher HLA in WA men did not contribute to the ethnic differences in HDL, as the differences in HDL were made up entirely of differences in HDL 3 and not HDL 2 .
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Hepatic Lipase and dyslipidemia interactions among genetic variants obesity gender and diet
Journal of Lipid Research, 2003Co-Authors: Samir S Deeb, Alberto Zambon, Molly C Carr, Amir F Ayyobi, John D BrunzellAbstract:Hepatic Lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia.
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visceral obesity Hepatic Lipase activity and dyslipidemia in type 1 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Shalamar D Sibley, Jerry P Palmer, Irl B Hirsch, John D BrunzellAbstract:Excessive weight gain in a subset of intensively treated Diabetes Control and Complications Trial (DCCT) subjects was associated with higher waist to hip ratio; higher triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (ApoB) in the presence of small-dense LDL; and decreased high-density lipoprotein 2 cholesterol (HDL2-C), suggesting that weight gain in these subjects resulted in higher intraabdominal fat (IAF), and an atherosclerotic dyslipidemia mediated through Hepatic Lipase activity (HL). Objectives were to investigate relationships between IAF, HL, and dyslipidemia and to relate IAF to previous body mass index change during the DCCT. Sixty-one subjects were studied approximately 4 yr after DCCT closeout. IAF was positively related to HL (P < 0.001). IAF positively correlated with logTG (P < 0.001) and ApoB (P < 0.001), and negatively with LDL relative flotation rate (P < 0.001) and logHDL2-C (P = 0.001). HL accounted for most of the relationship between IAF with logHD...
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Hepatic Lipase a marker for cardiovascular disease risk and response to therapy
Current Opinion in Lipidology, 2003Co-Authors: Alberto Zambon, Samir S Deeb, Paolo Pauletto, Gaetano Crepaldi, John D BrunzellAbstract:Purpose of review Hepatic Lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether Hepatic Lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of Hepatic Lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on Hepatic Lipase proposed roles in lipoprotein metabolism. Recent findings Twenty to 30% of individual variation of Hepatic Lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the Hepatic Lipase gene (LIPC). This polymorphism, via its impact on Hepatic Lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low Hepatic Lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high Hepatic Lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. Summary Convincing evidence shows that Hepatic Lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of Hepatic Lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.
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common Hepatic Lipase gene promoter variant determines clinical response to intensive lipid lowering treatment
Circulation, 2001Co-Authors: Alberto Zambon, Samir S Deeb, John E Hokanson, Greg B Brown, John D BrunzellAbstract:Background—The common −514 C→T polymorphism in the promoter region of the Hepatic Lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL2 cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects. Methods and Results—Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by 14C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL prom...
Scott M Grundy - One of the best experts on this subject based on the ideXlab platform.
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Hepatic Lipase lipc promoter polymorphism in men with coronary artery disease allele frequency and effects on Hepatic Lipase activity and plasma hdl c concentrations
Arteriosclerosis Thrombosis and Vascular Biology, 1999Co-Authors: Ralph V Shohet, Scott M Grundy, Gloria L Vega, Azam Anwar, Joaquin E Cigarroa, Jonathan CohenAbstract:Hepatic Lipase is an important determinant of plasma HDL concentration and LDL subclass distribution and may therefore influence susceptibility to coronary artery disease (CAD). To assess the effect of genetic variation in Hepatic Lipase activity on CAD susceptibility, we determined the frequency of the -514T allele of Hepatic Lipase in white men with CAD and in controls who did not have CAD. In men with CAD, postheparin plasma Hepatic Lipase activity was 15% to 20% lower in heterozygotes and 30% lower in homozygotes for the -514T allele. Allele frequencies were similar in cases and controls, however, and were consistent with Hardy-Weinberg expectation in both groups. This finding was confirmed in a second group comprising cases with premature symptomatic CAD and controls who were free of disease. These data indicate that a primary decrease in Hepatic Lipase activity of as much as 30% does not influence susceptibility to CAD in white men.
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Hepatic Lipase new insights from genetic and metabolic studies
Current Opinion in Lipidology, 1999Co-Authors: Jonathan Cohen, Gloria Lena Vega, Scott M GrundyAbstract:Hepatic Lipase catalyses the hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Genetic deficiency of this enzyme is associated with a unique plasma lipoprotein profile, characterized by hypertriglyceridemia and elevated concentrations of intermediate density lipopro
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Hepatic Lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men genetic and pharmacological evidence
Journal of Lipid Research, 1999Co-Authors: Scott M Grundy, Gloria Lena Vega, James D Otvos, David L Rainwater, Jonathan CohenAbstract:Several studies have reported an inverse relation- ship between Hepatic Lipase activity and plasma high density lipoprotein (HDL) cholesterol concentrations. The purpose of the present study was to determine whether genetic and pharmacological variation in Hepatic Lipase activity alters the distribution of HDL subclasses. Two independent ana- lytical methods (nuclear magnetic resonance and gradient gel electrophoresis) were used to compare HDL subclass distributions in 11 homozygotes for the 2 514C allele of he- patic Lipase and in 6 homozygotes for the 2 514T allele. Mean Hepatic Lipase activity was 45 6 15 mmol ? l 2 1 ? hr 2 1 in 2 514C homozygotes and 20 6 7 mmol ? l 2 1 ? hr 2 1 in 2 514T homozygotes. Both analytical methods indicated that HDL 2b was significantly higher and HDL 3a was significantly lower in 2 514T homozygotes than in 2 514C homozygotes. No dif- ferences were noted in the other HDL fractions (HDL 2a , HDL 3b , and HDL 3c ). To determine the effects of increased Hepatic Lipase activity, 20 men were given the synthetic ana- bolic steroid, stanozolol. Stanozolol treatment increased he- patic Lipase activity more than two-fold (38 6 18 to 85 6 25 mmol ? l 2 1 ? hr 2 1 ), and markedly reduced the plasma concen- trations of the larger HDL subclasses (HDL 2b and HDL 2a ).
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body mass index and Hepatic Lipase gene lipc polymorphism jointly influence postheparin plasma Hepatic Lipase activity
Journal of Lipid Research, 1998Co-Authors: Liangcai Nie, Jinping Wang, Luther T Clark, Aylmer Tang, Gloria Lena Vega, Scott M Grundy, Jonathan CohenAbstract:The -514 polymorphism in the Hepatic Lipase gene (LIPC) is associated with decreased Hepatic Lipase activity. In the present study, the interaction between body mass index (BMI), the -514 polymorphism, and Hepatic Lipase activity was examined in 118 white men and in 51 African American men. BMI was significantly positively correlated with Hepatic Lipase activity in both populations. BMI was similar in men with genetic differences in Hepatic Lipase activity, indicating that high Hepatic Lipase activity did not cause increased BMI. The data therefore suggest that high BMI leads to increased Hepatic Lipase activity. The actions of BMI and the -514 polymorphism on Hepatic Lipase activity appear to be additive and independent, rather than synergistic. This finding indicates that Hepatic Lipase activity is a multifactorial trait, determined in part by polymorphism within the LIPC gene as well as by factors that influence BMI.
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Hepatic Lipase activity is lower in African American men than in white American men: effects of 5' flanking polymorphism in the Hepatic Lipase gene (LIPC).
Journal of lipid research, 1998Co-Authors: Gloria Lena Vega, Luther T Clark, Aylmer Tang, Scott M Grundy, Santica M. Marcovina, Jonathan CohenAbstract:Plasma high density lipoprotein cholesterol (HDL-C) concentrations are higher in African American men than in white men, but the mechanism(s) responsible for this ethnic difference has not been elucidated. This study examined the relationship between Hepatic Lipase activity, plasma HDL-C concentrations, and a Hepatic Lipase polymorphism (-514T) in African American and white American men. Consistent with previous reports, plasma HDL-C concentrations were significantly higher in African American men than in white American men. Mean post-heparin plasma Hepatic Lipase activity was significantly lower in African American than in white American men (27 +/- 12 vs. 44 +/- 17 mmol x h(-1) x l(-1), P < 0.001). The -514T Hepatic Lipase allele was associated with low Hepatic Lipase activity in both populations, and was 3-fold more common among African Americans than white Americans. Taken together, these data suggest that genetic differences in Hepatic Lipase activity contribute to the differences in plasma HDL-C concentrations between African American men and white American men.
Samir S Deeb - One of the best experts on this subject based on the ideXlab platform.
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a novel method for measuring human lipoprotein Lipase and Hepatic Lipase activities in postheparin plasma
Journal of Lipid Research, 2008Co-Authors: Shigeyuki Imamura, Samir S Deeb, Junji Kobayashi, Katsuyuki Nakajima, S Sakasegawa, A Nohara, Tohru Noguchi, Masaaki Kawashiri, Akihiro Inazu, Hiroshi MabuchiAbstract:The objective of this study was to establish a new lipoprotein Lipase (LPL) and Hepatic Lipase (HL) activity assay method. Seventy normal volunteers were recruited. Lipase activities were assayed by measuring the increase in absorbance at 546 nm due to the quinoneine dye. Reaction mixture-1 (R-1) contained dioleoylglycerol solubilized with lauryldimethylaminobetaine, monoacylglycerol-specific Lipase, glycerolkinase, glycerol-3-phosphate oxidase, peroxidase, ascorbic acid oxidase, and apolipoprotein C-II (apoC-II). R-2 contained Tris-HCl (pH 8.7) and 4-aminoantipyrine. Automated assay of Lipase activities was performed with an automatic clinical analyzer. In the assay for HL + LPL activity, 160 μl R-1 was incubated at 37°C with 2 μl of sample for 5 min, and 80 μl R-2 was added. HL activities were measured under the same conditions without apoC-II. HL and LPL activities were also measured by the conventional isotope method and for HL mass by ELISA. Lipase activity detected in a 1.6 M NaCl-eluted fraction from a heparin-Sepharose column was enhanced by adding purified apoC-II in a dose-dependent manner, whereas that eluted by 0.8 M NaCl was not. Postheparin plasma-LPL and HL activities measured in the present automated method had high correlations with those measured by conventional activity and mass methods. This automated assay method for LPL and HL activities is simple and reliable and can be applied to an automatic clinical analyzer.
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transcriptional regulation of the human Hepatic Lipase lipc gene promoter
Journal of Lipid Research, 2006Co-Authors: Laura E Rufibach, Stephen A Duncan, Michele A Battle, Samir S DeebAbstract:Hepatic Lipase (HL) plays a key role in the metabolism of plasma lipoproteins, and its level of activity requires tight regulation, given the association of both low and high levels with atherosclerosis and coronary artery disease. However, little is known about the factors responsible for HL expression. Here, we report that the human Hepatic Lipase gene (LIPC) promoter is regulated by hepatocyte nuclear factor 4α (HNF4α), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), apolipoprotein A-I regulatory protein-1 (ARP-1), and hepatocyte nuclear factor 1α (HNF1α). Reporter analysis showed that HNF4α directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4. PGC-1α is capable of stimulating the HNF4α-dependent transactivation of the LIPC promoter. ARP-1 displaces HNF4α from the DR1 site and blocks its ability to activate the LIPC promoter. Induction by HNF1α requires the HNF1 binding site and upon cotransfection with HNF4α leads to an additive effect. In addition, the in vivo relevance of HNF4α in LIPC expression is shown by the ability of the HNF4α antagonist Medica 16 to repress endogenous LIPC mRNA expression. Furthermore, disruption of Hnf4α in mice prevents the expression of HL mRNA in liver. The overall effect these transcription factors have on HL expression will ultimately depend on the interplay between these various factors and their relative intracellular concentrations.
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ethnic differences in Hepatic Lipase and hdl in japanese black and white americans role of central obesity and lipc polymorphisms
Journal of Lipid Research, 2004Co-Authors: Molly C Carr, John D Brunzell, Samir S DeebAbstract:Hepatic Lipase activity (HLA) is a determinant of HDL levels, and a polymorphism in the Hepatic Lipase gene (LIPC) promoter (C-514T) has been hypothesized to account for higher HDL in blacks and Japanese compared with whites. To determine whether the polymorphism contributes to ethnic differences in HDL, we compared LIPC allele frequencies and HLA in Japanese American (JA; n = 84), black American (BA; n = 94), and white American (WA; n = 110) men and women. The LIPC polymorphism was associated with HLA in all cohorts (BA, P = 0.012; JA, P = 0.008; WA, P = 0.009). WA men had 49% and 58% higher HLA than BA and JA men, respectively (both P < 0.05), yet no differences in HLA were found between the women. The higher HLA in the WA men remained after adjustment for the LIPC polymorphism's effect on HLA (P = 0.037) but was erased after adjustment for waist-to-hip-ratio (P = 0.46). Although the WA men had lower HDL and HDL 3 than the JA and BA men (all P < 0.05 ), there were no differences in HDL 2 , implying that variance in HLA may not underlie the ethnic differences in HDL levels. These results suggest that 1) the LIPC promoter polymorphism contributes to variation in HLA and HDL 2 in the three ethnic groups; 2) WA men had higher HLA than BA and JA men, related to ethnic differences in central adiposity but not LIPC allele frequency; and 3) the higher HLA in WA men did not contribute to the ethnic differences in HDL, as the differences in HDL were made up entirely of differences in HDL 3 and not HDL 2 .
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Hepatic Lipase and dyslipidemia interactions among genetic variants obesity gender and diet
Journal of Lipid Research, 2003Co-Authors: Samir S Deeb, Alberto Zambon, Molly C Carr, Amir F Ayyobi, John D BrunzellAbstract:Hepatic Lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia.
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Hepatic Lipase a marker for cardiovascular disease risk and response to therapy
Current Opinion in Lipidology, 2003Co-Authors: Alberto Zambon, Samir S Deeb, Paolo Pauletto, Gaetano Crepaldi, John D BrunzellAbstract:Purpose of review Hepatic Lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether Hepatic Lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of Hepatic Lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on Hepatic Lipase proposed roles in lipoprotein metabolism. Recent findings Twenty to 30% of individual variation of Hepatic Lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the Hepatic Lipase gene (LIPC). This polymorphism, via its impact on Hepatic Lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low Hepatic Lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high Hepatic Lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. Summary Convincing evidence shows that Hepatic Lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of Hepatic Lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.
Silvia Santamarinafojo - One of the best experts on this subject based on the ideXlab platform.
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lipolytic and ligand binding functions of Hepatic Lipase protect against atherosclerosis in ldl receptor deficient mice
Journal of Lipid Research, 2007Co-Authors: Lita A Freeman, Marcelo Amar, Bryan H. Brewer, Silvia Santamarinafojo, Robert D Shamburek, Beverly Paigen, Herminia GonzaleznavarroAbstract:To elucidate the separate contributions of the lipolytic versus ligand-binding functions of Hepatic Lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL-WT) with mice expressing inactive HL (HL-S145G) in a background lacking endogenous HL and the LDLr (LDLr-KO×HL-KO). HL-WT and HL-S145G reduced (P
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the ligand binding function of Hepatic Lipase modulates the development of atherosclerosis in transgenic mice
Journal of Biological Chemistry, 2004Co-Authors: Herminia Gonzaleznavarro, Marcelo Amar, Bryan H. Brewer, Zengxuan Nong, Robert D Shamburek, Beverly Paigen, Jamila Najibfruchart, Silvia SantamarinafojoAbstract:To investigate the separate contributions of the lipolytic versus ligand-binding function of Hepatic Lipase (HL) to plasma lipoprotein metabolism and atherosclerosis, we compared mice expressing catalytically active wild-type HL (HL-WT) and inactive HL (HL-S145G) with no endogenous expression of mouse apoE or HL (E-KO × HL-KO, where KO is knockout). HL-WT and HL-S145G reduced plasma cholesterol (by 40 and 57%, respectively), non-high density lipoprotein cholesterol (by 48 and 61%, respectively), and apoB (by 36 and 44%, respectively) (p
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Hepatic Lipase lipoprotein metabolism and atherogenesis
Arteriosclerosis Thrombosis and Vascular Biology, 2004Co-Authors: Silvia Santamarinafojo, Herminia Gonzaleznavarro, Lita A Freeman, Elke Wagner, Zengxuan NongAbstract:The role of Hepatic Lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic Lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic Lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which Hepatic Lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that Hepatic Lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of Hepatic Lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for Hepatic Lipase. The concept of Hepatic Lipase as mainly a lipolytic enzyme that reduces atherogenic risk has evolved into that of a complex protein with multiple functions that, depending on genetic background and sites of expression, can have a variable effect on atherosclerosis.
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identification of mouse and human macrophages as a site of synthesis of Hepatic Lipase
Journal of Lipid Research, 2002Co-Authors: Herminia Gonzaleznavarro, André Bensadoun, Lita A Freeman, Zengxuan Nong, Katherine Peterson, Silvia SantamarinafojoAbstract:Hepatic Lipase (HL) is synthesized by the liver and is also present in steroidogenic tissues. As both a lipolytic enzyme and a ligand that facilitates the cellular uptake of lipoproteins, HL plays a major role in lipoprotein metabolism and may modulate atherogenic risk. However, HL has not been directly implicated in lesion development. In the present study we demonstrate that HL is also synthesized by mouse and human macrophages. Northern analysis and real time RT-PCR showed that HL mRNA is present in mouse peritoneal macrophages, RAW-264.7, and IC-21 cells. The levels of HL mRNA in mouse peritoneal macrophages were approximately 10-30% that of mouse liver. HL protein was identified by Western blot analyses in human monocyte-derived macrophages, THP, RAW-264.7, and mouse peritoneal macrophages following fractionation by heparin-sepharose affinity chromatography. These combined findings establish that HL is synthesized de novo by macrophages as well as liver, and raises the possibility that HL may have a direct role in the pathogenesis of atherosclerosis.
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Hepatic Lipase deficiency decreases the selective uptake of hdl cholesteryl esters in vivo
Journal of Lipid Research, 2000Co-Authors: Gilles Lambert, Marcelo Amar, Bryan H. Brewer, Robert D Shamburek, Pascal G P Martin, Jamila Fruchartnajib, Bernhard Foger, Silvia SantamarinafojoAbstract:Recent in vitro studies have provided evidence that Hepatic Lipase (HL) facilitates the selective uptake of HDL cholesteryl esters (CE), but the in vivo physiological relevance of this process has not been demonstrated. To evaluate the role that HL plays in facilitating the selective uptake of HDL-CE in vivo, we studied the metabolism of ( 3 H)CEt, 125 I-labeled apolipoprotein (apo) A-I, and 131 I- labeled apoA-II-labeled HDL in HL-deficient mice. Kinetic analysis revealed similar catabolism of 125 I-labeled apoA-I (as well as 131 I-labeled apoA-II) in C57BL controls and HL deficient mice, with fractional catabolic rates (FCR) of 2.17 6 0.15 and 2.16 6 0.11 d 2 1 (2.59 6 0.14 and 2.67 6 0.13 d 2 1 , respectively). In contrast, despite similar Hepatic scavenger receptor BI expression, HL-deficient mice had delayed clearance of ( 3 H)CEt compared to controls (FCR 5 3.66 6 0.29 and 4.41 6 0.18 d 2 1 , P , 0.05). The Hepatic accumula- tion of ( 3 H)CEt in HL-deficient mice (62.3 6 2.1% of total) was significantly less than in controls (72.7 6 3.0%), while the ( 3 H)CEt remaining in the plasma compartment in- creased (20.7 6 1.8% and 12.6 6 0.5%) ( P , 0.05, all). In summary, HL deficiency does not alter the catabolism of apoA-I and apoA-II but decreases the Hepatic uptake and the plasma clearance of HDL-CE. These data establish for the first time an important role for HL in facilitating the se- lective uptake of HDL-CE in vivo. —Lambert, G., M. J. A. Amar, P. Martin, J. Fruchart-Najib, B. Foger, R. D. Shambu- rek, H. B. Brewer, Jr., and S. Santamarina-Fojo. Hepatic Lipase deficiency decreases the selective uptake of HDL- cholesteryl esters in vivo. J. Lipid Res. 2000. 41: 667-672.