Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption

Abstract

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

“…Recently, two groups have independently identified mutations in either ABCG5 or ABCG8 as the cause of the rare, recessively inherited metabolic disease sitosterolaemia [10,11,12]. Patients with this disease develop xanthomas and premature atherosclerosis [24,25].…”

“…The genes encoding these transporters are highly expressed in the liver [9]. Mutations in the human genes encoding ABCG5 and ABCG8 have been shown to cause sitosterolaemia [10,11,12] with a reduced biliary secretion as well as a strongly enhanced intestinal absorption of plant sterols (sitosterol, campesterol). Indeed, ABCG5 and ABCG8 are also highly expressed in the intestine [9] and supposedly involved in efflux of plant sterols taken up by enterocytes back into the intestinal lumen, thereby preventing absorption.…”

“…Indeed, ABCG5 and ABCG8 are also highly expressed in the intestine [9] and supposedly involved in efflux of plant sterols taken up by enterocytes back into the intestinal lumen, thereby preventing absorption. Based on the fact that the efficiency of dietary cholesterol absorption is high in sitosterolaemia patients, a role of ABCG5 and ABCG8 in the control of cholesterol absorption efficiency has been proposed [10,11,12]. Accordingly, cholesterol absorption was reduced in mice over-expressing both transporters [7] and in mice in which expression of the transporters was induced by pharmacological means [13].…”

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 ATP binding cassette transporters G5 (ABCG5) and G8 (ABCG8) regulate cholesterol absorption from the intestine by their ability to work in tandem to excrete cholesterol and plant sterols from the enterocyte back into the intestinal lumen [15]. Impairment in function is associated with increased cholesterol and plant sterol absorption.…”

Cholesterol metabolism and therapeutic targets: Rationale for targeting multiple metabolic pathways

“…Mutations in either of these two proteins result in sitosterolemia. 14,15 Although it is well documented that the amount of cholesterol reaching the circulation from the lumen of the small bowel can be modulated by targeting events within either the intraluminal or intracellular phases of the absorption process, the newly discovered role of NPC1L1 in facilitating the uptake of sterols provides another target for regulating the enterohepatic movement of cholesterol.…”