Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol

Yu, Liqing; Li-Hawkins, Jia; Hammer, Robert E.; Berge, Knut Erik; Horton, Jay D.; Cohen, Jonathan C.; Hobbs, Helen H.

doi:10.1172/jci16001

Cited by 314 publications

(345 citation statements)

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“…Cholesterol secretion is one of the mechanisms by which the liver excretes cholesterol. Because the sterol transporters ABCG5 and ABCG8 mediate cholesterol secretion into bile 21,22,31 , plant sterols have been thought to up regulate the expression of these two genes in the liver and thus cholesterol excretion, thereby lowering plasma cholesterol concentrations. Paradoxically, the present study showed that stanol esters (0·7 % in the diet) decreased liver ABCG5 mRNA levels and appeared to lower ABCG8 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

“…The role of ABCG5 and ABCG8 transporters in cholesterol efflux has further been demonstrated in transgenic mice by expressing both human and mouse ABCG5 and ABCG8 genes. Results showed approximately 50 % reductions in cholesterol absorption and marked increases in biliary cholesterol secretion and faecal neutral sterol excretion compared with their wild-type littermates 22 . In contrast, the ABCG5-/-and ABCG8-/-mice presented increased absorption of dietary sterols and impaired biliary * Corresponding author: Dr Peter J. H. Jones, fax þ1 204 474 7552, email peter_jones@umanitoba.ca Abbreviations: Ch-Con, control diet with 0·25 % cholesterol; Con, control diet; Sta, Ch-Con diet with 1 % plant stanols; Ste, Ch-Con diet with 1 % plant sterols; SteF, sterols esterified to fish oil; StaA, stanols esterified to ascorbic acid.…”

mentioning

confidence: 95%

“…The role of ABCG5 and ABCG8 transporters in cholesterol efflux has further been demonstrated in transgenic mice by expressing both human and mouse ABCG5 and ABCG8 genes. Results showed approximately 50 % reductions in cholesterol absorption and marked increases in biliary cholesterol secretion and faecal neutral sterol excretion compared with their wild-type littermates 22 . In contrast, the ABCG5-/-and ABCG8-/-mice presented increased absorption of dietary sterols and impaired biliary sterol excretion and had plasma sitosterol levels 30-fold higher than their wild-type littermates 21 .…”

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confidence: 95%

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Hypocholesterolaemic effects of plant sterol analogues are independent of ABCG5 and ABCG8 transporter expressions in hamsters

et al. 2007

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The hypolipidaemic effects of plant sterols are well established. However, mechanisms by which plant sterols lower plasma cholesterol levels, particularly at the molecular level, have not been clearly elucidated. The objective of the present study was to determine whether different plant sterol analogues reduce plasma cholesterol levels by up regulating the sterol transporters ABCG5 and ABCG8 in the liver and/or small intestine. Male Golden Syrian hamsters were divided into eight groups. Groups 1 and 2 were fed a maize starch -casein -sucrose-based diet that did not contain cholesterol (control; Con) or the Con diet with the addition of 0·25 % cholesterol (Ch-Con). Groups 3 -8 were fed the Ch-Con diet supplemented with 1 % plant sterols, 1 % plant stanols, 1 % of a plant sterol and stanol mixture (50:50), 1·76 % plant sterol -fish oil esters, or 0·71 or 1·43 % stanol -ascorbic acid esters, respectively. After 5 weeks, the Ch-Con diet up regulated the ABCG5 mRNA expression and tended (P¼ 0·083) to increase ABCG8 mRNA expression in the liver, but did not affect both genes' expression in the small intestine compared with the Con diet. Hamsters fed 0·7 % stanol esters showed lower plasma cholesterol levels (P,0·001) and also lower liver ABCG5 mRNA expression (P, 0·05) compared with the Ch-Con diet. Plant stanols, stanol esters, and sterol esters did not affect the ABCG5 or ABCG8 mRNA expressions in the liver and intestine although they reduced plasma cholesterol levels. These results suggest that plant sterols and their derivatives reduce plasma cholesterol levels independently from the mRNA expression of ABCG5 and ABCG8 transporters. Cholesterol: Plant sterols: ABCG5: ABCG8: Hamsters It has been well documented that dietary supplementation with plant sterols and stanols reduces plasma cholesterol levels in human subjects and animals 1 -9 . Plant sterols and stanols are not water soluble and possess low solubility in fats. It is believed that solubility characteristics affect the bioavailability and cholesterol-lowering efficacy of sterols and stanols. Thus, a large body of research has been conducted attempting to modify the structure of plant sterols and stanols, and the esterification to fatty acids 10,11 or ascorbic acid has been extensively studied in the past years 12 -14 . Accordingly, several different analogues of plant sterols and stanols are currently available as functional food ingredients or nutraceuticals.The interference with cholesterol incorporation into micelles has long been thought to be the possible mechanism by which plant sterols and stanols inhibit cholesterol absorption 15,16 . However, this mechanism cannot explain the observation that plasma cholesterol levels were significantly decreased in hamsters after plant sterols were injected intraperitoneally 17 . Recent advances in molecular research have indicated that the sterol transporter-mediated cholesterol efflux in the enterocytes and cholesterol secretion in the liver may play important roles in cholesterol absorption and metabolism 18...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

“…The role of ABCG5 and ABCG8 transporters in cholesterol efflux has further been demonstrated in transgenic mice by expressing both human and mouse ABCG5 and ABCG8 genes. Results showed approximately 50 % reductions in cholesterol absorption and marked increases in biliary cholesterol secretion and faecal neutral sterol excretion compared with their wild-type littermates 22 . In contrast, the ABCG5-/-and ABCG8-/-mice presented increased absorption of dietary sterols and impaired biliary sterol excretion and had plasma sitosterol levels 30-fold higher than their wild-type littermates 21 .…”

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confidence: 95%

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Hypocholesterolaemic effects of plant sterol analogues are independent of ABCG5 and ABCG8 transporter expressions in hamsters

et al. 2007

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“…These are members of the large ABC family of transmembrane proteins, 40 and were recently shown to be essential for cholesterol efflux from the liver to the bile canaliculus and from the intestine. 41 The ABC transporters have also been implicated in mediating estrogen actions on cholesterol transport. 42,43 In mice, although no direct assessment of the effects of estrogen on ABC transporters has yet been reported, one study 26 had suggested that ABCG5/G8 are not modulated by estrogen in mice.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

et al. 2005

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OBJECTIVE:The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs a and b, both of which have been involved in the metabolic actions of estrogen. This study aimed at determining the identity of the ER involved in the beneficial metabolic actions of ACOL. DESIGN AND MEASUREMENTS: ACOL was administered for 4 weeks to male and female wild-type and ERa knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. RESULTS: ERa KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERa KO mice. ACOL reduced plasma cholesterol in female wild-type mice (À27%), whereas the compound remained ineffective in their ERa KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. CONCLUSION: The beneficial metabolic actions of the SERM ACOL on adiposity and on plasma and liver lipids are entirely due to its interaction with the ERa.

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“…Membranes were washed thrice in TTBS and incubated with horseradish peroxidase-conjugated V. W. Bloks et al: Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated 105 secretion of cholesterol into bile is coupled to that of phospholipids in a process that is, in part, controlled by bile salt secretion [6]. Recent studies, however, indicate that specific ABC transporters, i.e., Abcg5 and Abcg8, are involved in biliary cholesterol secretion [7,8]. The genes encoding these transporters are highly expressed in the liver [9].…”

mentioning

confidence: 99%

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

Bloks¹,

Waarde²,

Verkade³

et al. 2004

Diabetologia

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Aim/hypothesis. Type I diabetes is associated with altered hepatic bile formation and increased intestinal cholesterol absorption. The aim of this study was to evaluate whether altered expression of the ATP-Binding Cassette half-transporters Abcg5 and Abcg8, recently implicated in control of both hepatobiliary cholesterol secretion and intestinal cholesterol absorption, contributes to changed cholesterol metabolism in experimental diabetes. Methods. mRNA and protein expression of Abcg5 and Abcg8 were determined in the liver and intestine of rats with streptozotozin-induced diabetes and related to relevant metabolic parameters in plasma, liver and bile. Results. Hepatic mRNA expression of both Abcg5 (−76%) and Abcg8 (−71%) was reduced in diabetic rats when compared to control rats. In spite of increased HDL cholesterol, considered a major source of biliary cholesterol, secretion of the sterol into bile relative to that of bile salts was reduced by 65% in diabetic animals. Intestinal mRNA expression of Abcg5 (−47%) and Abcg8 (−43%) as well as Abcg5 protein contents were also reduced in insulin-deficient animals. This was accompanied by a three-to four-fold increase in plasma β-sitosterol and campesterol concentrations and by a doubling of the calculated apparent cholesterol absorption. These effects partially normalized upon insulin supplementation. Conclusion/interpretation. Our data indicate that effects of insulin-deficiency on bile composition and cholesterol absorption in rats are, at least partly, attributable to changes in hepatic and intestinal Abcg5 and Abcg8 expression. [Diabetologia (2004) Type I diabetes mellitus is associated with specific changes in cholesterol metabolism in humans [1] and in experimental animals [2,3], including increased concentrations of plasma cholesterol, enhanced conversion of cholesterol into bile salts and an enhanced intestinal cholesterol absorption. The hepatobiliary pathway is of crucial importance for the maintenance of cholesterol homeostasis [4]. Bile salts that are secreted by the liver into the intestinal lumen are required for intestinal absorption of dietary cholesterol. The majority of bile salts is subsequently reabsorbed from the intestine and returns to the liver for re-secretion into the bile. The relatively small fraction of bile salts that escapes intestinal absorption is compensated for by de novo synthesis from cholesterol in the liver. Secondly, bile contains considerable amounts of free cholesterol. Since only a part of biliary cholesterol is reabsorbed from the intestine [5], the biliary pathway contributes to a major extent to cholesterol turnover. It is well-established that

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Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol

Cited by 314 publications

References 39 publications

Hypocholesterolaemic effects of plant sterol analogues are independent of ABCG5 and ABCG8 transporter expressions in hamsters

Hypocholesterolaemic effects of plant sterol analogues are independent of ABCG5 and ABCG8 transporter expressions in hamsters

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

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

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