Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity

The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 men and 119 women) divided into tertiles by baseline serum cholestanol-to-cholesterol ratio (≤118.3 and ≥147.7 102 × mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P <0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest cholestanol tertile (P < 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers (P < 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp.In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene. The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 men and 119 women) divided into tertiles by baseline serum cholestanol-to-cholesterol ratio (≤118.3 and ≥147.7 102 × mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P <0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest cholestanol tertile (P < 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers (P < 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp. In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene. Serum cholesterol level is regulated by cholesterol absorption and synthesis. In different study populations (1Kesäniemi Y.A. Miettinen T.A. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population.Eur. J. Clin. Invest. 1987; 17: 391-395Google Scholar, 2Miettinen T.A. Tilvis R.S. Kesäniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Google Scholar, 3Gylling H. Miettinen T.A. Absorption and metabolism of cholesterol in familial hypercholesterolaemia.Clin. Sci. 1989; 76: 297-301Google Scholar), serum total and LDL cholesterol levels are associated positively with cholesterol absorption efficiency and negatively with cholesterol synthesis, suggesting that the higher the cholesterol absorption level, the higher the serum cholesterol level and the lower cholesterol synthesis. Cholesterol absorption efficiency and cholesterol synthesis are inversely related, and they can reliably be depicted by serum noncholesterol sterol levels (2Miettinen T.A. Tilvis R.S. Kesäniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Google Scholar). However, it is not known which of these variables, cholesterol absorption or synthesis, is the one primarily regulated. It has been shown that both absorption efficiency and synthesis of cholesterol are genetically determined (4Gylling H. Miettinen T.A. Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption.J. Lipid Res. 2002; 43: 1472-1476Google Scholar, 5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar), such that in coronary families, the heredity of cholesterol metabolism can be predicted by serum cholestanol-to-cholesterol ratio, a surrogate marker of cholesterol absorption efficiency (4Gylling H. Miettinen T.A. Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption.J. Lipid Res. 2002; 43: 1472-1476Google Scholar). We have recently shown that cholesterol absorption correlates positively and cholesterol synthesis correlates negatively with insulin sensitivity (6Pihlajamäki J. Gylling H. Miettinen T.A. Laakso M. Insulin resistance with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men.J. Lipid Res. 2004; 45: 507-512Google Scholar), but the link between insulin action and cholesterol metabolism has remained unknown. Phytosterolemia, an inherited disease with high absorption and low biliary secretion of cholesterol and plant sterols, is caused by a mutation in genes regulating ABCG5 (G5) or ABCG8 (G8) transporter proteins (7Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.Science. 2000; 290: 1771-1775Google Scholar, 8Lee M.H. Lu K. Hazard S. Yu H. Shulenin S. Hidaka H. Kojima H. Allikmets R. Sakuma N. Pegoraro R. Srivastava A.K. Salen G. Dean M. Patel S.B. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.Nat. Genet. 2001; 27: 79-83Google Scholar). Two sequence variations (D19H and T400K) in the G8 gene were shown to be associated with lower serum plant sterol levels in a normolipidemic family study (5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar). In addition, in mice the overexpression of the human G5 and G8 genes reduced plasma plant sterol levels and cholesterol absorption and increased hepatic cholesterol synthesis and biliary cholesterol secretion (9Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.J. Clin. Invest. 2002; 110: 671-680Google Scholar). Two questions now arise. First, do healthy subjects with high cholesterol absorption efficiency have a sequence variation in the G5 or G8 gene resulting in increased intestinal absorption of sterols? Second, could polymorphisms in these genes regulate insulin action? To answer these questions, we recruited noncoronary subjects with mild to moderate hypercholesterolemia and with cholesterol absorption efficiency ranging from low to high assayed with serum cholestanol-to-cholesterol ratio and evaluated the effect of common sequence variants of the G5 and G8 genes (5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar, 10Hubacek J.A. Berge K.E. Cohen J.C. Hobbs H.H. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.Hum. Mutat. 2001; 18: 359-360Google Scholar) on cholesterol absorption and insulin action in these subjects. Two-hundred sixty-three mildly to moderately hypercholesterolemic subjects (serum cholesterol < 7.5 mmol/l), 144 men and 119 women with a mean age of 53.1 ± 0.5 years (mean ± SEM) were recruited to the study from former studies carried out at the Departments of Clinical Nutrition and Medicine, University of Kuopio (11Haffner S.M. Karhapää P. Mykkänen L. Laakso M. Insulin resistance, body fat distribution, and sex hormones in men.Diabetes. 1994; 43: 212-219Google Scholar), the Department of Medicine, University of Helsinki (12Rajaratnam R.A. Gylling H. Miettinen T.A. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women.J. Am. Coll. Cardiol. 2000; 35: 1185-1191Google Scholar), and the Kuopio Research Institute of Exercise Medicine (Table 1). Thirty-six subjects had hypertension, seven subjects were on thyroid hormone therapy from 15 to 26 years, and they all were euthyroid. Two subjects had symptomless coeliacia under good control. None of the subjects had diabetes, hepatic or malignant disease, or lipid-lowering therapy. Thirty-nine women had hormone replacement therapy, and seven used oral contraceptives or had a hormone-releasing intrauterine device. Sixteen subjects used β-blocking agents, 10 used calcium channel blockers, 21 used angiotensin-converting enzyme or receptor blocking agents, and 13 used diuretics for hypertension. Fifty-four were smokers. The subjects were advised to keep their normal habitual diet and daily drug treatment unchanged. Seventy-one healthy men participated in a hyperinsulinemic euglycemic clamp study to evaluate insulin metabolism (11Haffner S.M. Karhapää P. Mykkänen L. Laakso M. Insulin resistance, body fat distribution, and sex hormones in men.Diabetes. 1994; 43: 212-219Google Scholar).TABLE 1Demographic data, plasma glucose and serum insulin, serum lipids, squalene, and noncholesterol sterols in tertiles by serum cholestanol-to-cholesterol ratio in the study population (n = 263)VariableProbandP aSignificance between the probands of different tertiles analyzed with one-way ANOVA.Low Absorbers (n = 87)Intermediate Absorbers (n = 89)High Absorbers (n = 87)Male/female48/3953/3643/44Age (years) 54.4 ± 0.7 53.1 ± 0.8 51.7 ± 1.20.117Body mass index (kg/m2) 28.1 ± 0.4 26.6 ± 0.4 24.6 ± 0.3<0.001Plasma glucose (mmol/l) 5.79 ± 0.07 5.61 ± 0.08 5.38 ± 0.07<0.001Serum insulin (mU/l) 11.03 ± 0.75 8.01 ± 0.46 6.84 ± 0.39<0.001Serum cholesterol (mmol/l) 5.71 ± 0.11 5.80 ± 0.11 5.75 ± 0.120.874LDL cholesterol (mmol/l) 3.64 ± 0.09 3.79 ± 0.11 3.67 ± 0.120.549HDL cholesterol (mmol/l) 1.36 ± 0.04 1.45 ± 0.04 1.56 ± 0.040.002Serum triglycerides (mmol/l) 1.61 ± 0.14 1.23 ± 0.06 1.12 ± 0.07<0.001Squaleneb102 × mmol/mol cholesterol. 32 ± 1 31 ± 1 30 ± 10.500Cholestenolb102 × mmol/mol cholesterol. 18 ± 1 15 ± 1 14 ± 1<0.001Desmosterolb102 × mmol/mol cholesterol. 82 ± 2 78 ± 2 73 ± 30.002Lathosterolb102 × mmol/mol cholesterol. 217 ± 5 170 ± 5 138 ± 5<0.001Campesterolb102 × mmol/mol cholesterol. 174 ± 6 232 ± 8 330 ± 13<0.001Sitosterolb102 × mmol/mol cholesterol. 101 ± 3 123 ± 4 172 ± 6<0.001Cholestanolb102 × mmol/mol cholesterol. 101 ± 1 132 ± 1 177 ± 3<0.001Apolipoproteins E2/E3/E4cApolipoprotein E genotypes E2 (2/3, 2/4), E3 (3/3), and E4 (4/3, 4/4).5/48/296/55/254/52/24Values shown are means ± SEM. For cholesterol, to obtain mg/dl, by for triglycerides, by For insulin, to obtain by between the probands of different tertiles analyzed with one-way 102 × mmol/mol E genotypes E2 (2/3, 2/4), E3 (3/3), and E4 (4/3, in a shown are means ± SEM. For cholesterol, to obtain mg/dl, by for triglycerides, by For insulin, to obtain by was an for the and the subjects their The study was by the of the Department of Medicine, University of University of and the Kuopio University Serum and cholesterol and triglycerides were analyzed with and glucose and serum insulin Insulin were with and and serum and were analyzed by Serum cholesterol and precursors squalene, desmosterol, and cholesterol synthesis (2Miettinen T.A. Tilvis R.S. Kesäniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Google Scholar), and the plant sterols and cholestanol of cholesterol), sterols cholesterol absorption efficiency (2Miettinen T.A. Tilvis R.S. Kesäniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Google Scholar, H. Miettinen T.A. Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption.J. Lipid Res. 2002; 43: 1472-1476Google Scholar), were with on a an T.A. P. sterols and in with G. and Cholesterol in and Scholar). The squalene and noncholesterol sterol were in of 102 × mmol/mol cholesterol ratio in the the squalene and sterol by the cholesterol of the to the of different serum cholesterol The of insulin sensitivity was evaluated by the hyperinsulinemic euglycemic clamp and in 71 healthy clamp R.A. J.D. R. clamp a for insulin secretion and J. Scholar) was a (11Haffner S.M. Karhapää P. Mykkänen L. Laakso M. Insulin resistance, body fat distribution, and sex hormones in men.Diabetes. 1994; 43: 212-219Google Scholar). baseline a of insulin was the 10 to plasma insulin to the level, it was by a insulin of glucose was at for the by the of glucose at to glucose at 5 The mean of glucose the of the clamp were used to the of glucose The for variation of glucose was the clamp common polymorphisms of the G5 and G8 genes were assayed by and polymorphism (5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar, L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.J. Clin. Invest. 2002; 110: 671-680Google Scholar) in subjects. The used were and The in 1 and in 2 of the G8 gene were analyzed with the polymorphism The was analyzed by and polymorphism K. M. H. K. by of E in a Clin. Scholar) in subjects. were with the for The are means ± SEM. and of were or was for that were not or in and or were used for was a of was used for with that were not different or were not in or were were with the the or the The subjects were divided into tertiles by baseline serum cholestanol-to-cholesterol ratio and cholestanol tertiles and 102 × mmol/mol cholesterol), that the tertiles subjects with low to high absorption efficiency of cholesterol. The in the different tertiles shown in 1 were on or and hormone replacement therapy, or oral In both BMI, plasma glucose, serum insulin, and serum triglycerides were negatively and HDL cholesterol was positively to cholestanol tertiles (Table was used a for HDL = of the synthesis marker sterols (cholestenol, desmosterol, and but not of squalene, were and of the absorption markers and sitosterol) were positively to an in serum cholestanol level, and for cholestenol and desmosterol, all remained for the in the tertile in the metabolic syndrome. not the The of the different polymorphisms were in in the study and in of different cholesterol absorption polymorphisms were in with = < The D19H polymorphism of the G8 gene was in the cholestanol tertiles = < that the 19H allele was common in the tertile with the tertiles (Table not the ABCG5 and ABCG8 of common polymorphisms of the ABCG8 and ABCG5 genes in subjects with mild to moderate hypercholesterolemia in the tertiles of cholestanol-to-cholesterol ratio (n = Absorbers (n = 87)Intermediate Absorbers (n = Absorbers (n = = (P < 26 = (P < in a The 19H allele of the G8 gene was associated with lower serum total cholesterol ± ± < and LDL cholesterol ± ± < higher serum cholestenol and and lower serum sitosterol, and cholestanol in subjects the allele (Table with the of the G8 gene were associated with lower serum level and lower plasma glucose level were in age or between the The were in men and common polymorphisms of the ABCG8 genes and of glucose and cholesterol metabolism in probands (n = with mild to moderate (years) 53.1 ± ± ± ± 0.7 ± 0.7 ± ± ± ± ± mass index (kg/m2) ± ± ± 0.4 ± 26.6 ± ± ± ± ± ± between the and the analyzed with the or the a < < < glucose (mmol/l) ± 0.05 ± ± 0.08 ± 0.05 ± 0.06 ± ± 0.06 ± between the and the analyzed with the or the a < < < ± ± insulin (mU/l) ± ± ± ± ± ± ± ± ± ± cholesterol (mmol/l) ± 0.07 ± between the and the analyzed with the or the a < < < ± ± 0.08 ± 0.09 ± ± 0.08 ± ± ± cholesterol (mmol/l) ± 0.07 ± between the and the analyzed with the or the a < < < ± 0.11 ± 0.07 ± 0.08 ± ± 0.08 ± ± ± cholesterol (mmol/l) 1.45 ± ± ± 0.05 ± ± ± ± ± ± ± triglycerides (mmol/l) ± 0.06 ± ± 0.07 ± 0.07 ± 0.09 ± between the and the analyzed with the or the a < < < ± 0.06 ± ± ± × mmol/mol cholesterol. 31 ± 1 31 ± 2 30 ± 1 31 ± 1 31 ± 1 31 ± 1 31 ± 1 30 ± 1 31 ± 1 30 ± × mmol/mol cholesterol. 15 ± 1 ± 15 ± 1 ± 1 ± 1 15 ± 1 ± 1 ± 1 15 ± 1 18 ± × mmol/mol cholesterol. ± 1 ± 3 78 ± 2 78 ± 1 ± 2 ± 2 78 ± 2 78 ± 2 ± 1 ± × mmol/mol cholesterol. ± 4 ± ± 6 174 ± 4 ± 5 172 ± 5 ± 5 174 ± 5 ± 4 ± × mmol/mol cholesterol. ± 174 ± ± 13 ± 8 ± ± 10 ± ± ± 8 ± × mmol/mol cholesterol. 138 ± 3 ± 138 ± ± 4 ± 4 ± 5 132 ± 4 132 ± 5 ± 4 ± × mmol/mol cholesterol. ± 2 ± ± 4 ± 3 138 ± 3 ± 3 ± 3 ± 4 138 ± 2 132 ± shown are means ± SEM. For cholesterol, to obtain mg/dl, by for triglycerides, by For insulin, to obtain by between the and the analyzed with the or the between the and the analyzed with the or the a < < < < < < 102 × mmol/mol cholesterol. in a shown are means ± SEM. For cholesterol, to obtain mg/dl, by for triglycerides, by For insulin, to obtain by The 604E allele of the G5 gene was associated with high BMI, serum insulin level, and serum cholestenol ratio and with low serum and (Table In men, the were different between the with or the 604E ± ± = serum insulin ± ± 0.5 < serum cholestenol ± 1 15 ± = serum ± ± = serum ± 18 ± = serum ± ± = and serum cholestanol ± 5 138 ± = serum sterols are in of 102 × mmol/mol However, with a the higher serum insulin and cholestenol and the lower serum ratio in men with but not the 604E allele remained In serum cholestenol ratio was higher in the subjects with the In the subgroup of 71 men in the hyperinsulinemic euglycemic clamp had the 604E The glucose was ± 3 in the subjects with the allele and ± 2 in the subjects the allele (P = The metabolic were in the cholestanol tertiles in subjects with and the D19H polymorphism of the G8 gene 1). In subjects with the 19H serum ratio was not increased with cholestanol in subjects with the gene, was an Serum cholestenol ratio was increased with the cholestanol tertiles in subjects with the 19H and the in the tertile between subjects with and the allele was (P < the D19H polymorphism of the ABCG8 gene and the Q604E polymorphism of the ABCG5 gene, the polymorphisms associated with cholesterol absorption and insulin were in we analyzed the effect of genotypes of these polymorphisms on the levels of cholestanol marker of cholesterol and insulin marker of insulin that the D19H polymorphism of the G8 gene was associated with cholesterol absorption and the Q604E polymorphism of the G5 gene was associated with The in the study that in a mildly to moderately hypercholesterolemic noncoronary subjects with the lowest tertile of serum cholestanol-to-cholesterol ratio, a surrogate marker of low cholesterol absorption had characteristics of the metabolic high plasma glucose and serum and insulin high levels of the cholesterol synthesis markers in and low HDL cholesterol association was in coronary (4Gylling H. Miettinen T.A. Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption.J. Lipid Res. 2002; 43: 1472-1476Google Scholar). Second, polymorphisms of the G8 and G5 genes were associated with different of glucose and cholesterol of the could be of the polymorphisms to be to glucose and cholesterol The D19H polymorphism of the G8 gene was associated with cholesterol and the Q604E polymorphism of the G5 gene was associated with insulin The 19H allele of the G8 gene subjects with lower serum total and LDL cholesterol level, lower cholesterol absorption marker sterols, and higher cholesterol synthesis marker The polymorphism of the G5 gene was associated with low cholesterol absorption marker level, high serum insulin level, and glucose suggesting insulin resistance in We have shown that coronary subjects with low cholesterol absorption markers are and have high cholesterol synthesis marker sterols T.A. Gylling H. for the Finnish of the sterols and cholesterol by treatment in coronary to serum 2002; Scholar) and high serum triglycerides and low HDL cholesterol levels T.A. Gylling H. S. serum cholestanol of coronary in subgroup of Finnish Scholar). The study these in noncoronary subjects and in that high plasma glucose, the normal and high serum insulin levels are in subjects with low absorption and high synthesis of cholesterol. Low cholesterol absorption and high synthesis has been in subjects with glucose levels H. Miettinen T.A. of glucose with cholesterol absorption and synthesis in men.Diabetes. 45: Scholar) and in with 2 Gylling Miettinen T.A. to cholesterol metabolism of 2002; Scholar), in cholesterol absorption was increased with of insulin resistance P. Gylling H. Miettinen T.A. a of the metabolic low cholesterol J. Clin. 2000; Scholar). it from studies in different populations that low cholesterol absorption efficiency and high cholesterol synthesis are of the insulin resistance syndrome. has been in normoglycemic men in insulin clamp studies (6Pihlajamäki J. Gylling H. Miettinen T.A. Laakso M. Insulin resistance with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men.J. Lipid Res. 2004; 45: 507-512Google Scholar). The of the regulation of cholesterol absorption efficiency or cholesterol synthesis is genetically regulated. In of G5 and G8 in a to in the absorption of dietary plant sterols, an in plasma and a in biliary cholesterol secretion L. Hammer R.E. Li-Hawkins J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. of and in mice their in biliary cholesterol Sci. 2002; Scholar). In addition, on 14 and 2 in which are from the G5 and G8 have been shown to regulate plasma levels Lutjohann D. von Bergmann K. A.K. Salen G. on 14 and from regulate plasma plant sterol levels in a × Sci. 2002; Scholar). In mutations in the G5 and G8 genes in high intestinal absorption of cholesterol and In a family study of a normal population by Berge (5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar), the D19H of the G8 gene in a different low serum sitosterol, and suggesting sterol However, association with serum levels was of cholesterol synthesis, to cholesterol could be to cholesterol The the the polymorphism of the G8 gene was associated with high serum and to cholesterol and low and the polymorphism of the G8 gene was associated with high serum total cholesterol (5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar), of which could be in the the D19H polymorphism of the G8 gene, the the by Berge (5Berge K.E. von Bergmann K. Lutjohann D. Guerra R. Grundy S.M. Hobbs H.H. Cohen J.C. Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.J. Lipid Res. 2002; 43: 486-494Google Scholar) that serum absorption marker sterols were lower in subjects with In addition, a in the study was that the D19H polymorphism was in the tertile in the cholestanol In addition, subjects with polymorphism had low serum total and LDL cholesterol the that serum cholesterol level is regulated by cholesterol absorption efficiency the D19H polymorphism in noncoronary subjects with mild to moderate the increased serum ratio that cholesterol synthesis was was a cholesterol The cholesterol synthesis in these subjects the of therapy K. binding transporter G5 and G8 genotypes and plasma levels and treatment with Lipid Res. 2004; 45: Scholar). In the the of the D19H to the of serum ratio from the in cholestanol suggesting an effect on cholesterol and the in cholesterol synthesis in these subjects could be It can be that the G8 gene regulates cholesterol absorption in subjects and that polymorphism in low cholesterol absorption high synthesis of cholesterol, and low serum total and LDL cholesterol The polymorphism of the G5 gene was associated with insulin at in has not been Two important questions genes that regulate cholesterol absorption could regulate insulin and with we have these that low absorption of cholesterol is at regulated the ABCG8 gene, the ABCG5 gene with insulin The of subjects to these with However, these be of they a link at the level between of hypercholesterolemia and insulin study was by from the Finnish of the Finnish Research the Kuopio University the Kuopio University the Research and the The of and is