Hepatic Lipase Gene Variant eC514C>T Is Associated With Lipoprotein and Insulin Sensitivity Response to Regular Exercise
http://www.100md.com
糖尿病学杂志 2005年第7期
1 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana
2 Department of Pediatrics, "F. Fede" Second University of Naples, Napoli, Italy
3 Lipid Research Center, CHUL Medical Research Center, Queebec, Canada
4 Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri
5 Laboratory of Physiological Hygiene and Exercise Science, School of Kinesiology, University of Minnesota, Minneapolis, Minnesota
6 Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, Missouri
7 Department of Kinesiology, Indiana University, Bloomington, Indiana
8 Keck School of Medicine, University of Southern California, Los Angeles, California
9 Quebec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Queebec, Canada
ABSTRACT
We investigated the associations between the hepatic lipase gene (LIPC) eC514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity (Si) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and Si were measured in the sedentary state and posteCexercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n = 662). The LIPC eC514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and posteCexercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HDL3, and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low posteCexercise training. Baseline Si was not associated with the LIPC genotypes. However, training-induced improvements in Si both in blacks and whites were greater in CC homozygotes (+1.25 ± 0.2 and +0.22 ± 0.2 e蘒 · mineC1 · mleC1) than in the TT genotype (+0.27 ± 0.3 and eC0.97 ± 0.3 e蘒 · mineC1 · mleC1) (P = 0.008 and P = 0.002, respectively). The LIPC eC514C allele was associated with higher hepatic lipase activity in sedentary and physically active states and better Si responses to regular exercise both in black and white individuals. The benefits from an exercise program on Si are likely to be substantial in the general population given the high frequency of the LIPC eC514C allele, particularly in whites.
Hepatic lipase hydrolyzes triglyceride and phospholipids from high-, intermediate-, and low-density lipoproteins, transforming them into smaller and denser particles, and promotes the cellular uptake of HDL cholesterol (1). The hepatic lipase gene (LIPC), located on chromosome 15q21-q23, is expressed in the liver. Hepatic lipase has been the subject of recent reviews for its molecular (1) and pathophysiologic significance in obesity, dyslipidemia, and atherogenesis (2). There is familial resemblance for plasma postheparin lipoprotein lipase (LPL) and postheparin hepatic lipase activities (3), and exercise trainingeCinduced improvement in insulin sensitivity (Si) correlates with decreased postheparin hepatic lipase activity.
Genetic polymorphisms in the LIPC gene are associated with postheparin hepatic lipase activity (4eC6). Four frequently reported genetic variants in the LIPC promoter are in almost complete linkage disequilibrium, forming two haplotypes (2). The less common T allele in the eC514C>T variant has been associated with a 30eC40% decrease in postheparin hepatic lipase activity and higher HDL cholesterol levels (4). However, the relevance of this polymorphism for the transcriptional regulation of the LIPC gene remains controversial (7eC10).
The benefits of regular physical activity in decreasing the risk of developing insulin resistance and coronary heart disease (CHD) are well documented, although individual responses vary considerably (11,12). Regular exercise affects lipid-lipoprotein profiles and peripheral glucose utilization (12,13). We investigated associations between the LIPC eC514C>T variant and plasma lipoprotein levels, Si and postheparin hepatic lipase, and postheparin LPL activities in a biracial cohort under sedentary-state conditions and their responses to endurance exercise training.
RESEARCH DESIGN AND METHODS
The Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study design and methods have been described previously (14). Briefly, the HERITAGE Family Study was designed to investigate the role of genetic factors in cardiovascular, metabolic, and hormonal responses to endurance training in white and black families. All subjects were required to be sedentary and in good health to participate in the HERITAGE Family Study, as well as to fulfill a series of inclusion criteria (14). For the present study we only excluded individuals without genotype or phenotype data. Data from 219 black adults (79 males and 140 females) and 443 white adults (218 males and 225 females) were available. Each institutional review board of the HERITAGE Family Study research consortium approved the study protocol. Written informed consent was obtained from each participant.
Exercise training program.
The exercise training program has been described in detail previously (14,15). Briefly, the exercise intensity of the 20-week program was customized for each participant based on the heart rateeCoxygen uptake relationship measured at baseline. During the first 2 weeks, the subjects trained at a heart rate corresponding to 55% of VO2max for 30 min per session. Duration was gradually increased to 50 min per session and intensity to the heart rate associated with 75% of the baseline VO2max. These conditions were then sustained for the last 6 weeks. Training frequency was three times per week, and all training sessions were performed under supervision on cycle ergometers at the participating clinical centers. The subjects were instructed not to change their diet during the intervention.
Phenotype measurements.
All phenotypes were measured at baseline and after the 20-week exercise training program.
Measurement of Si.
A frequently sampled intravenous glucose tolerance test was performed as described (16) in the morning after a 12-h overnight fast and no less than 24 h after the last exercise session. From the frequently sampled intravenous glucose tolerance test data, Si was derived using the MINMOD Millennium computer program (17). Si measures the ability of plasma insulin to enhance the net disappearance of glucose from plasma. These analyses were described previously (16).
Postheparin lipase activities, lipids, and lipoproteins.
Postheparin LPL and postheparin hepatic lipase activities were measured by the modified Nilsson-Ehle and Ekman method, as previously reported (13). Activity is expressed as nanomoles of free fatty acid released divided by milliliters of plasma divided by minutes. Lipid, lipoprotein, and apolipoprotein (apo) assays have been reported previously in detail (3).
Genetic analyses.
Genomic DNA was extracted from lymphoblastoid cell lines using standard procedures. Genotyping for the LIPC eC514C>T polymorphism (dbSNP rs#1800588) was performed using the TaqMan allelic discrimination method. Details for PCR conditions and primer/probe sequences are available upon request.
Statistical analyses.
All statistical analyses were performed with the SAS Statistical Software Package (release 8.2; SAS Institute, Cary, NC). A 2 test was used to compare allele frequencies and to test whether the genotype distributions were in Hardy-Weinberg equilibrium. Associations between the LIPC eC514C>T genotypes and phenotypes were analyzed using a MIXED procedure. Nonindependence among family members was adjusted using a "sandwich estimator" as described in previous HERITAGE publications. Because of the skewed distributions, baseline plasma triglyceride, VLDL cholesterol, and HDL cholesterol were normalized with log transformation. The Si data derived from the MINMOD Millennium model required a square root transformation to approximate a normal distribution. All analyses were done separately in blacks and whites. All baseline data were adjusted for age, sex, and BMI, whereas the training responses were also adjusted for the respective baseline values.
RESULTS
The LIPC eC514C allele frequency was 0.516 (blacks) and 0.796 (whites). Genotype distributions were in Hardy-Weinberg equilibrium. The LIPC eC514C>T polymorphism showed a strong association with postheparin hepatic lipase activity, which was 40% higher in the CC homozygotes at baseline (P 0.0001) and posttraining (P 0.0001) in both ethnic groups (Fig. 1).
The LIPC eC514C>T polymorphism was also associated with postheparin LPL activity. The black CC homozygotes had 32 and 21% lower postheparin LPL activity before and after exercise training than the LIPC TT homozygotes (P = 0.0005 and 0.009, respectively). White CC homozygotes had 12 and 19% lower postheparin LPL activity before and after exercise training than TT homozygotes (P = 0.0004 and <0.0001, respectively) (Fig. 2).
Associations of LIPC eC514C>T genotypes with lipids and lipoprotein concentrations in the sedentary state and their training responses in blacks and whites are shown in Table 1. In blacks, the TT homozygotes exhibited higher baseline HDL cholesterol, HDL3, and apoA-1 concentrations than the CC homozygotes. The LIPC eC514 polymorphism was also associated with apoB (P = 0.04) training response, with the greatest reduction observed in the TT homozygotes. White TT homozygotes also had higher HDL cholesterol and apoA-1 concentrations in the sedentary state, as well as significantly higher plasma trigylceride, VLDL cholesterol, LDL cholesterol, and apoB concentrations.
There were no differences in Si between the LIPC eC514 genotypes in blacks and whites in the sedentary state (Table 2). However, trainingeCinduced improvements in Si in blacks and whites were greater in the CC homozygotes (+1.25 ± 0.2 and +0.22 ± 0.2 e蘒 · mineC1 · mleC1) than in the TT genotype (+0.27 ± 0.3 and eC0.97 ± 0.32 e蘒 · mineC1 · mleC1), with heterozygotes showing intermediary values.
DISCUSSION
Our data demonstrate significant associations between the LIPC eC514C>T polymorphism and plasma postheparin hepatic lipase and postheparin LPL activities and lipoprotein levels in the sedentary state as well as with endurance trainingeCinduced changes in Si. Several studies have shown that DNA sequence variations at the LIPC locus contribute to postheparin hepatic lipase plasma levels and the lipoprotein profile (2,6). A recent meta-analysis concluded that the LICP eC514C>T polymorphism is important in determining hepatic lipase activity and HDL concentration (18). However, associations between this polymorphism and changes in lipoprotein levels or Si in response to exercise training have not been addressed before.
The LIPC eC514TT homozygotes had 30% lower postheparin hepatic lipase activity compared with the CC homozygotes, and the genotype accounted for 7eC8% of the variation in postheparin hepatic lipase activity. This association remained after exercise training. Blacks had lower postheparin hepatic lipase activity, an ethnic difference found in both sexes and concordant with previous observations (19,20). Several in vitro studies have reported a 30eC40% reduction in transcriptional activity in cells transfected with the T allele compared with the C allele (rev. in 2). Other studies found no functional effects of this allelic variant, perhaps because of differences in cell lines, transfection efficiencies, and reporter vectors used (7,8,10). Overall, our data strengthen reports that associate postheparin hepatic lipase activity with the LIPC eC514C>T polymorphism (4,7,9). Recently, a prospective cohort study found that the TT genotype had increased susceptibility to CHD in sedentary or moderately physically active subjects but not among the vigorously active (21).
Individuals carrying the LIPC eC514T allele had higher postheparin LPL activity at baseline and after exercise training. We have reported earlier higher postheparin LPL activity in blacks in the sedentary state (22) and that increased LPL activity was associated with an improved lipoprotein-lipid profile in response to an exercise training program (13). Here we report that the TT homozygotes had 25% higher LPL activity after exercise training than the CC homozygotes. The increase in LPL activity after endurance exercise training in combination with the higher HDL cholesterol observed in the TT homozygotes could impact CHD risk.
Hepatic lipase deficiency modifies the lipoprotein profile. It has been related to increased plasma cholesterol and trigylceride levels and mass redistribution within HDL particles (2). The most consistent finding in hepatic lipase deficiency is increased HDL2. The LIPC eC250G>A variant, which is in complete linkage disequilibrium with the LIPC eC514C>T, also leads to decreased hepatic lipase activity in the A allele carriers and to buoyant LDL particles and high HDL cholesterol (4). We found associations between the LIPC eC514C>T polymorphism and the lipoprotein profile in the sedentary state, with higher HDL cholesterol and apoA-1 levels in the TT homozygotes. Although there were no significant associations with other lipoproteins, the association for HDL cholesterol levels remained significant in the trained state. Increased risk of atherosclerosis has been associated with the LIPC eC514T allele, and CC homozygotes benefit the most from intensive lipid-lowering therapy (4,23).
This study is the first to examine the associations between the LIPC eC514C>T genotypes and Si and the responses of postheparin lipase to an exercise training intervention. The LIPC eC514C>T genotypes showed associations with Si and postheparin hepatic lipase activity after exercise training. The enhanced Si after exercise training, primarily in the CC homozygotes, was associated with higher postheparin hepatic lipases activity. Remarkably, these Si differences appeared only in response to exercise training. The second European Atherosclerosis Research Study reported that T allele carriers have the lowest glucose tolerance (24). Recently, the LIPC-205G>A polymorphism, which is in complete linkage disequilibrium with the LIPC eC514C>T, has been reported to predict the conversion from impaired glucose tolerance to type 2 diabetes in a 3-year follow-up lifestyle intervention (25).
The mechanisms behind the association of the LIPC eC514C>T polymorphism and Si are unclear. Changes in blood lipids in response to decreased postheparin hepatic lipase activity and increased postheparin LPL activity may accompany changes in intramyocellular lipid storage, affecting Si (26). Several regulatory elements have been identified in the rat LIPC promoter, and consensus analysis with the human sequence suggests that the LIPC eC514C>T variant may be in a DNA motif containing the sequences necessary for insulin/glucose responses. Insulin regulation of the LIPC gene could be mediated by either upstream stimulatory factor or sterol regulatory elementeCbinding protein-1c transcription factors, which bind to the E-box motif located in the LIPC promoter region at eC514 bp, although this has not been demonstrated (9). One could speculate that human variation in Si response to exercise training associated with the LIPC genotype is the consequence of transcriptional effects on the LIPC gene by insulin and the binding (or lack of) of transcription factors to the E-box motif.
Finally, the present study suggests that regular exercise may not influence the lipoprotein profile or improve Si at the same rate for all individuals and that the efficacy of regular exercise could be related in part to the LIPC eC514C>T genotype. C allele carriers may not only have more clinical benefit from intensive lipid-lowering therapy, as reported (4), but are more likely to benefit from an exercise training program. The improvement in Si with regular exercise in individuals with the LIPC eC514C allele has significant clinical applications due to its high frequency in various populations (4,5,7). Arguably, screening for T allele carriers may allow the identification of subjects at elevated risk requiring individualized therapeutic strategies to decrease cardiovascular and metabolic disease risks.
In summary, results from the HERITAGE Family Study indicate that the C allele at eC514 in the promoter region of the LIPC gene is associated with higher postheparin hepatic lipase activity and better Si response to regular exercise. The benefits on Si from an exercise program could be of considerable importance in the general population given the high frequency of the LIPC eC514C allele.
ACKNOWLEDGMENTS
The HERITAGE Family Study is supported by National Heart, Lung, and Blood Institute Grants HL-45670 (to C.B.), HL-47323 (to A.S.L.), HL-47317 (to D.C.R.), HL-47327 (to J.S.S.), and HL-47321 (to J.H.W.). A.S.L. is partially supported by the Henry L. Taylor endowed Professorship in Exercise Science and Health Enhancement, and C.B. is partially supported by the George A. Bray Chair in Nutrition.
Gratitude is expressed to Dr. Jack H. Wilmore for the critical reading of the manuscript and his comments. We thank Anik Boudreau for her expert contribution to the single nucleotide polymorphism genotyping. Thanks are expressed to Nina Laidlaw for her editorial support.
apo, apolipoprotein; CHD, coronary heart disease; HERITAGE, Health, Risk Factors, Exercise Training, and Genetics; LPL, lipoprotein lipase
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2 Department of Pediatrics, "F. Fede" Second University of Naples, Napoli, Italy
3 Lipid Research Center, CHUL Medical Research Center, Queebec, Canada
4 Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri
5 Laboratory of Physiological Hygiene and Exercise Science, School of Kinesiology, University of Minnesota, Minneapolis, Minnesota
6 Departments of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, Missouri
7 Department of Kinesiology, Indiana University, Bloomington, Indiana
8 Keck School of Medicine, University of Southern California, Los Angeles, California
9 Quebec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Queebec, Canada
ABSTRACT
We investigated the associations between the hepatic lipase gene (LIPC) eC514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity (Si) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and Si were measured in the sedentary state and posteCexercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n = 662). The LIPC eC514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and posteCexercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HDL3, and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low posteCexercise training. Baseline Si was not associated with the LIPC genotypes. However, training-induced improvements in Si both in blacks and whites were greater in CC homozygotes (+1.25 ± 0.2 and +0.22 ± 0.2 e蘒 · mineC1 · mleC1) than in the TT genotype (+0.27 ± 0.3 and eC0.97 ± 0.3 e蘒 · mineC1 · mleC1) (P = 0.008 and P = 0.002, respectively). The LIPC eC514C allele was associated with higher hepatic lipase activity in sedentary and physically active states and better Si responses to regular exercise both in black and white individuals. The benefits from an exercise program on Si are likely to be substantial in the general population given the high frequency of the LIPC eC514C allele, particularly in whites.
Hepatic lipase hydrolyzes triglyceride and phospholipids from high-, intermediate-, and low-density lipoproteins, transforming them into smaller and denser particles, and promotes the cellular uptake of HDL cholesterol (1). The hepatic lipase gene (LIPC), located on chromosome 15q21-q23, is expressed in the liver. Hepatic lipase has been the subject of recent reviews for its molecular (1) and pathophysiologic significance in obesity, dyslipidemia, and atherogenesis (2). There is familial resemblance for plasma postheparin lipoprotein lipase (LPL) and postheparin hepatic lipase activities (3), and exercise trainingeCinduced improvement in insulin sensitivity (Si) correlates with decreased postheparin hepatic lipase activity.
Genetic polymorphisms in the LIPC gene are associated with postheparin hepatic lipase activity (4eC6). Four frequently reported genetic variants in the LIPC promoter are in almost complete linkage disequilibrium, forming two haplotypes (2). The less common T allele in the eC514C>T variant has been associated with a 30eC40% decrease in postheparin hepatic lipase activity and higher HDL cholesterol levels (4). However, the relevance of this polymorphism for the transcriptional regulation of the LIPC gene remains controversial (7eC10).
The benefits of regular physical activity in decreasing the risk of developing insulin resistance and coronary heart disease (CHD) are well documented, although individual responses vary considerably (11,12). Regular exercise affects lipid-lipoprotein profiles and peripheral glucose utilization (12,13). We investigated associations between the LIPC eC514C>T variant and plasma lipoprotein levels, Si and postheparin hepatic lipase, and postheparin LPL activities in a biracial cohort under sedentary-state conditions and their responses to endurance exercise training.
RESEARCH DESIGN AND METHODS
The Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study design and methods have been described previously (14). Briefly, the HERITAGE Family Study was designed to investigate the role of genetic factors in cardiovascular, metabolic, and hormonal responses to endurance training in white and black families. All subjects were required to be sedentary and in good health to participate in the HERITAGE Family Study, as well as to fulfill a series of inclusion criteria (14). For the present study we only excluded individuals without genotype or phenotype data. Data from 219 black adults (79 males and 140 females) and 443 white adults (218 males and 225 females) were available. Each institutional review board of the HERITAGE Family Study research consortium approved the study protocol. Written informed consent was obtained from each participant.
Exercise training program.
The exercise training program has been described in detail previously (14,15). Briefly, the exercise intensity of the 20-week program was customized for each participant based on the heart rateeCoxygen uptake relationship measured at baseline. During the first 2 weeks, the subjects trained at a heart rate corresponding to 55% of VO2max for 30 min per session. Duration was gradually increased to 50 min per session and intensity to the heart rate associated with 75% of the baseline VO2max. These conditions were then sustained for the last 6 weeks. Training frequency was three times per week, and all training sessions were performed under supervision on cycle ergometers at the participating clinical centers. The subjects were instructed not to change their diet during the intervention.
Phenotype measurements.
All phenotypes were measured at baseline and after the 20-week exercise training program.
Measurement of Si.
A frequently sampled intravenous glucose tolerance test was performed as described (16) in the morning after a 12-h overnight fast and no less than 24 h after the last exercise session. From the frequently sampled intravenous glucose tolerance test data, Si was derived using the MINMOD Millennium computer program (17). Si measures the ability of plasma insulin to enhance the net disappearance of glucose from plasma. These analyses were described previously (16).
Postheparin lipase activities, lipids, and lipoproteins.
Postheparin LPL and postheparin hepatic lipase activities were measured by the modified Nilsson-Ehle and Ekman method, as previously reported (13). Activity is expressed as nanomoles of free fatty acid released divided by milliliters of plasma divided by minutes. Lipid, lipoprotein, and apolipoprotein (apo) assays have been reported previously in detail (3).
Genetic analyses.
Genomic DNA was extracted from lymphoblastoid cell lines using standard procedures. Genotyping for the LIPC eC514C>T polymorphism (dbSNP rs#1800588) was performed using the TaqMan allelic discrimination method. Details for PCR conditions and primer/probe sequences are available upon request.
Statistical analyses.
All statistical analyses were performed with the SAS Statistical Software Package (release 8.2; SAS Institute, Cary, NC). A 2 test was used to compare allele frequencies and to test whether the genotype distributions were in Hardy-Weinberg equilibrium. Associations between the LIPC eC514C>T genotypes and phenotypes were analyzed using a MIXED procedure. Nonindependence among family members was adjusted using a "sandwich estimator" as described in previous HERITAGE publications. Because of the skewed distributions, baseline plasma triglyceride, VLDL cholesterol, and HDL cholesterol were normalized with log transformation. The Si data derived from the MINMOD Millennium model required a square root transformation to approximate a normal distribution. All analyses were done separately in blacks and whites. All baseline data were adjusted for age, sex, and BMI, whereas the training responses were also adjusted for the respective baseline values.
RESULTS
The LIPC eC514C allele frequency was 0.516 (blacks) and 0.796 (whites). Genotype distributions were in Hardy-Weinberg equilibrium. The LIPC eC514C>T polymorphism showed a strong association with postheparin hepatic lipase activity, which was 40% higher in the CC homozygotes at baseline (P 0.0001) and posttraining (P 0.0001) in both ethnic groups (Fig. 1).
The LIPC eC514C>T polymorphism was also associated with postheparin LPL activity. The black CC homozygotes had 32 and 21% lower postheparin LPL activity before and after exercise training than the LIPC TT homozygotes (P = 0.0005 and 0.009, respectively). White CC homozygotes had 12 and 19% lower postheparin LPL activity before and after exercise training than TT homozygotes (P = 0.0004 and <0.0001, respectively) (Fig. 2).
Associations of LIPC eC514C>T genotypes with lipids and lipoprotein concentrations in the sedentary state and their training responses in blacks and whites are shown in Table 1. In blacks, the TT homozygotes exhibited higher baseline HDL cholesterol, HDL3, and apoA-1 concentrations than the CC homozygotes. The LIPC eC514 polymorphism was also associated with apoB (P = 0.04) training response, with the greatest reduction observed in the TT homozygotes. White TT homozygotes also had higher HDL cholesterol and apoA-1 concentrations in the sedentary state, as well as significantly higher plasma trigylceride, VLDL cholesterol, LDL cholesterol, and apoB concentrations.
There were no differences in Si between the LIPC eC514 genotypes in blacks and whites in the sedentary state (Table 2). However, trainingeCinduced improvements in Si in blacks and whites were greater in the CC homozygotes (+1.25 ± 0.2 and +0.22 ± 0.2 e蘒 · mineC1 · mleC1) than in the TT genotype (+0.27 ± 0.3 and eC0.97 ± 0.32 e蘒 · mineC1 · mleC1), with heterozygotes showing intermediary values.
DISCUSSION
Our data demonstrate significant associations between the LIPC eC514C>T polymorphism and plasma postheparin hepatic lipase and postheparin LPL activities and lipoprotein levels in the sedentary state as well as with endurance trainingeCinduced changes in Si. Several studies have shown that DNA sequence variations at the LIPC locus contribute to postheparin hepatic lipase plasma levels and the lipoprotein profile (2,6). A recent meta-analysis concluded that the LICP eC514C>T polymorphism is important in determining hepatic lipase activity and HDL concentration (18). However, associations between this polymorphism and changes in lipoprotein levels or Si in response to exercise training have not been addressed before.
The LIPC eC514TT homozygotes had 30% lower postheparin hepatic lipase activity compared with the CC homozygotes, and the genotype accounted for 7eC8% of the variation in postheparin hepatic lipase activity. This association remained after exercise training. Blacks had lower postheparin hepatic lipase activity, an ethnic difference found in both sexes and concordant with previous observations (19,20). Several in vitro studies have reported a 30eC40% reduction in transcriptional activity in cells transfected with the T allele compared with the C allele (rev. in 2). Other studies found no functional effects of this allelic variant, perhaps because of differences in cell lines, transfection efficiencies, and reporter vectors used (7,8,10). Overall, our data strengthen reports that associate postheparin hepatic lipase activity with the LIPC eC514C>T polymorphism (4,7,9). Recently, a prospective cohort study found that the TT genotype had increased susceptibility to CHD in sedentary or moderately physically active subjects but not among the vigorously active (21).
Individuals carrying the LIPC eC514T allele had higher postheparin LPL activity at baseline and after exercise training. We have reported earlier higher postheparin LPL activity in blacks in the sedentary state (22) and that increased LPL activity was associated with an improved lipoprotein-lipid profile in response to an exercise training program (13). Here we report that the TT homozygotes had 25% higher LPL activity after exercise training than the CC homozygotes. The increase in LPL activity after endurance exercise training in combination with the higher HDL cholesterol observed in the TT homozygotes could impact CHD risk.
Hepatic lipase deficiency modifies the lipoprotein profile. It has been related to increased plasma cholesterol and trigylceride levels and mass redistribution within HDL particles (2). The most consistent finding in hepatic lipase deficiency is increased HDL2. The LIPC eC250G>A variant, which is in complete linkage disequilibrium with the LIPC eC514C>T, also leads to decreased hepatic lipase activity in the A allele carriers and to buoyant LDL particles and high HDL cholesterol (4). We found associations between the LIPC eC514C>T polymorphism and the lipoprotein profile in the sedentary state, with higher HDL cholesterol and apoA-1 levels in the TT homozygotes. Although there were no significant associations with other lipoproteins, the association for HDL cholesterol levels remained significant in the trained state. Increased risk of atherosclerosis has been associated with the LIPC eC514T allele, and CC homozygotes benefit the most from intensive lipid-lowering therapy (4,23).
This study is the first to examine the associations between the LIPC eC514C>T genotypes and Si and the responses of postheparin lipase to an exercise training intervention. The LIPC eC514C>T genotypes showed associations with Si and postheparin hepatic lipase activity after exercise training. The enhanced Si after exercise training, primarily in the CC homozygotes, was associated with higher postheparin hepatic lipases activity. Remarkably, these Si differences appeared only in response to exercise training. The second European Atherosclerosis Research Study reported that T allele carriers have the lowest glucose tolerance (24). Recently, the LIPC-205G>A polymorphism, which is in complete linkage disequilibrium with the LIPC eC514C>T, has been reported to predict the conversion from impaired glucose tolerance to type 2 diabetes in a 3-year follow-up lifestyle intervention (25).
The mechanisms behind the association of the LIPC eC514C>T polymorphism and Si are unclear. Changes in blood lipids in response to decreased postheparin hepatic lipase activity and increased postheparin LPL activity may accompany changes in intramyocellular lipid storage, affecting Si (26). Several regulatory elements have been identified in the rat LIPC promoter, and consensus analysis with the human sequence suggests that the LIPC eC514C>T variant may be in a DNA motif containing the sequences necessary for insulin/glucose responses. Insulin regulation of the LIPC gene could be mediated by either upstream stimulatory factor or sterol regulatory elementeCbinding protein-1c transcription factors, which bind to the E-box motif located in the LIPC promoter region at eC514 bp, although this has not been demonstrated (9). One could speculate that human variation in Si response to exercise training associated with the LIPC genotype is the consequence of transcriptional effects on the LIPC gene by insulin and the binding (or lack of) of transcription factors to the E-box motif.
Finally, the present study suggests that regular exercise may not influence the lipoprotein profile or improve Si at the same rate for all individuals and that the efficacy of regular exercise could be related in part to the LIPC eC514C>T genotype. C allele carriers may not only have more clinical benefit from intensive lipid-lowering therapy, as reported (4), but are more likely to benefit from an exercise training program. The improvement in Si with regular exercise in individuals with the LIPC eC514C allele has significant clinical applications due to its high frequency in various populations (4,5,7). Arguably, screening for T allele carriers may allow the identification of subjects at elevated risk requiring individualized therapeutic strategies to decrease cardiovascular and metabolic disease risks.
In summary, results from the HERITAGE Family Study indicate that the C allele at eC514 in the promoter region of the LIPC gene is associated with higher postheparin hepatic lipase activity and better Si response to regular exercise. The benefits on Si from an exercise program could be of considerable importance in the general population given the high frequency of the LIPC eC514C allele.
ACKNOWLEDGMENTS
The HERITAGE Family Study is supported by National Heart, Lung, and Blood Institute Grants HL-45670 (to C.B.), HL-47323 (to A.S.L.), HL-47317 (to D.C.R.), HL-47327 (to J.S.S.), and HL-47321 (to J.H.W.). A.S.L. is partially supported by the Henry L. Taylor endowed Professorship in Exercise Science and Health Enhancement, and C.B. is partially supported by the George A. Bray Chair in Nutrition.
Gratitude is expressed to Dr. Jack H. Wilmore for the critical reading of the manuscript and his comments. We thank Anik Boudreau for her expert contribution to the single nucleotide polymorphism genotyping. Thanks are expressed to Nina Laidlaw for her editorial support.
apo, apolipoprotein; CHD, coronary heart disease; HERITAGE, Health, Risk Factors, Exercise Training, and Genetics; LPL, lipoprotein lipase
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