Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Groen, Albert K.; Bloks, Vincent W.; Bandsma, Robert; Ottenhoff, Roelof; Chimini, Giovanna; Kuipers, Folkert

doi:10.1172/jci200112473

Cited by 133 publications

(81 citation statements)

References 58 publications

(37 reference statements)

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“…Despite heavy Oil Red O-positive lipid staining in the liver, the SV129 ABCA1 Ϫ/Ϫ mouse had no accumulation of cholesterol ester in the liver or intestine (57,59). Interestingly, the DBA ABCA1 Ϫ/Ϫ mouse had either no accumulation or a significant decrease in cholesterol ester levels in the liver and intestine, depending on the study (61,62).…”

Section: Discussionmentioning

confidence: 98%

“…In SV129/C57BL/6 hybrid mice, loss of ABCA1 resulted in a small but significant decrease in intestinal cholesterol absorption on a cholesterolfree diet, with an associated increase in the fecal neutral sterol excretion (57,59). In contrast, another ABCA1 Ϫ/Ϫ mouse, created in a DBA background, showed an increase in cholesterol absorption on both a chow and Western diet, and the fecal excretion of neutral sterols was unaffected (58,60,61). Despite heavy Oil Red O-positive lipid staining in the liver, the SV129 ABCA1 Ϫ/Ϫ mouse had no accumulation of cholesterol ester in the liver or intestine (57,59).…”

Section: Discussionmentioning

confidence: 99%

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ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens

Mulligan

Flowers

Tebon

et al. 2003

Journal of Biological Chemistry

113

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The ATP-binding cassette transporter A1 (ABCA1) participates in the efflux of cholesterol from cells. It remains unclear whether ABCA1 functions to efflux cholesterol across the basolateral or apical membrane of the intestine. We used a chicken model of ABCA1 dysfunction, the Wisconsin hypoalpha mutant (WHAM) chicken, to address this issue. After an oral gavage of radioactive cholesterol, the percentage appearing in the bloodstream was reduced by 79% in the WHAM chicken along with a 97% reduction in the amount of tracer in high density lipoprotein. In contrast, the percentage of radioactive cholesterol absorbed from the lumen into the intestine was not affected by the ABCA1 mutation. Liver X receptor (LXR) agonists have been inferred to decrease cholesterol absorption through activation of ABCA1 expression. However, the LXR agonist T0901317 decreased cholesterol absorption equally in both wild type and WHAM chickens, indicating that the effect of LXR activation on cholesterol absorption is independent of ABCA1. The ABCA1 mutation resulted in accumulation of radioactive cholesterol ester in the intestine and the liver of the WHAM chicken (5.0-and 4.4-fold, respectively), whereas biliary lipid concentrations were unaltered by the WHAM mutation. In summary, ABCA1 regulates the efflux of cholesterol from the basolateral but not apical membrane in the intestine and the liver.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens

Mulligan

Flowers

Tebon

et al. 2003

Journal of Biological Chemistry

113

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“…Taken together, our data do not support impaired SR-BI-mediated HDL uptake as a cause of cholesterol hyposecretion in diabetic rats. In fact, our recent observation that cholesterol secretion is unaffected in Abca1 null mice lacking HDL [35] strongly argues against a regulatory role of cholesterol delivery. A concise overview of various models of cholesterol hypo-and hypersecretion indicated that, at least in mice, biliary cholesterol secretion strongly correlates with hepatic Abcg5/Abcg8 expression [21].…”

Section: Discussionmentioning

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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“…Although previous work has shown that LXR ligands reduce cholesterol absorption (6), the mechanism behind this effect is not entirely clear. Studies on ABCA1 knockout mice have reported that loss of this protein does not alter cholesterol or bile acid excretion (26). Other studies have shown that the lipoproteins primarily affected by loss of ABCA1 expression on Western diet are HDL and very-low-density lipoprotein (27).…”

Section: Figmentioning

confidence: 99%

Synthetic LXR ligand inhibits the development of atherosclerosis in mice

Joseph

McKilligin

Pei

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

863

657

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The nuclear receptors LXR␣ and LXR␤ have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR ؊͞؊ mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE ؊͞؊ mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR ؊͞؊ and apoE ؊͞؊ mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.R ecent work has identified the nuclear receptors LXR␣ and LXR␤ as central regulators of lipid homeostasis. The physiologic ligands for these receptors are likely to be specific intermediates in the cholesterol biosynthetic pathway such as 24(S),25-epoxycholesterol (1-3). LXR␣ is expressed primarily in liver, intestine, adipose tissue, and macrophages, whereas LXR␤ is expressed in many cell types (4). In peripheral cells such as macrophages, LXRs seem to coordinate a physiologic response to cellular cholesterol loading. LXRs directly control transcription of several genes involved in the cholesterol efflux pathway, including ATP-binding cassette (ABC) A1 (5-8), ABCG1 (9), and apolipoprotein E (apoE) (10). In the intestine, ligand activation of LXR͞RXR heterodimers dramatically reduces dietary cholesterol absorption, an effect postulated to be mediated by ABCA1 (6).In the liver, LXRs seem to regulate both cholesterol and fatty acid metabolism. Mice carrying a targeted disruption of the Lxr␣ gene fail to induce transcription of the gene encoding cholesterol 7␣-hydroxylase (CYP7A1) in response to dietary cholesterol, implicating LXRs in the control of bile acid synthesis (11). Mice lacking LXR␣ were also observed to be deficient in expression of fatty acid synthase, steroyl-coA desaturase 1, acyl-coA carboxylase, and sterol regulatory element binding protein-1, suggesting an additional role in lipogenesis. This hypothesis was supported by the subsequent demonstration that the synthetic LXR ligand T1317 induces expression of lipogenic genes and raises plasma trigly...

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Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Cited by 133 publications

References 58 publications

ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens

ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens

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

Synthetic LXR ligand inhibits the development of atherosclerosis in mice

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