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

Abstract

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 ( Յ 118.3 and Ն 147.7 10 2 ؋ 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 Ͻ 0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest cholestanol tertile ( P Ͻ 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers ( P Ͻ 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 Ͻ 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 (1-3), 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 (2). 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 (4, 5), 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 (4). We have recently shown that cholesterol absorption correlates positively and cholesterol synthesis correlates negatively with insulin sensitivity (6), 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 (7,8). Two sequence variations (D19H a...

Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann–Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein

“…The promoter region of the gene encoding MTTP has a negative insulin response element [31] and we have previously speculated that this may influence the raised levels of MTTP mRNA which we find in diabetes. It is interesting to see that polymorphisms in the Q604E allele of the ABCG5 gene in men were associated with insulin resistance [32]. In streptozotocin-induced diabetes in rats it has been shown that intestinal mRNA expression of ABCG5 and ABCG8 and ABCG5 protein content were reduced as was ABCG5 and ABCG8 expression in the liver [33].…”

Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease

“…25 Indeed, there are published data about an association between the D19H variant and serum cholesterol levels. 26,27 Moreover, recent genome-wide studies identified an association of LDL cholesterol with proxies to D19H and the other ABCG8 variant rs4245791. 22,23 This effect could be confirmed in the present study (online-only Data Supplement Figure VI), albeit the association of D19H (and the other variants we identified) with serum cholesterol levels was only weak, and effects on phytosterols remained highly significant after normalization to cholesterol (Table) or adjustment to LDL cholesterol (online-only Data Supplement Table XVII).…”

Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance

“…At the physiological level, the serum cholesterol level is maintained mainly by de novo synthesis in the liver and partially by the absorption efficiency of the intestine (Wang 2007;Davis et al 2004;Temel et al 2007). Based on the findings of Gylling et al (2004) and Kajinami et al (2004a), subjects with D19H/19H have a lower cholesterol absorption efficiency but respond more to statin treatment than D19 subjects. Upon comparing our results with those in previous reports, we rationally assumed that consuming a higher ratio of plant sterols to cholesterol in the diet may influence the relative absorption efficiency of cholesterol in subjects with D19H variants, causing a much lower cholesterol absorption and therefore increasing hepatic cholesterol biosynthesis, thus resulting in higher serum total cholesterol and LDL-C levels than those of D19 variants.…”