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Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor.

Plösch T, Bloks VW, Terasawa Y, Berdy S, Siegler K, Van Der Sluijs F, Kema IP, Groen AK, Shan B, Kuipers F, Schwarz M, Schwartz M


BACKGROUND AND AIMS: Mutations in either adenosine triphosphate- binding cassette (ABC) half-transporter G5 or G8 cause sitosterolemia. It has been proposed that ABCG5/ABCG8 heterodimers mediate secretion of plant sterols and cholesterol by hepatocytes into bile and their efflux from enterocytes into the intestinal lumen. METHODS: To test whether deficiency of ABCG5 alone is sufficient to induce sitosterolemia, Abcg5-null mice were generated and characterized with respect to sterol metabolism. RESULTS: Abcg5 deficiency was associated with strongly elevated plasma levels of beta-sitosterol (37-fold) and campesterol (7.7-fold) as well as reduced plasma cholesterol concentrations (-40%). Retention of orally administered [(3)H]beta-sitosterol in the intestinal wall (+550%) and plasma (+640%) was higher in Abcg5-null mice than in wild-type controls. Surprisingly, high plasma beta-sitosterol and campesterol concentrations were even further elevated in Abcg5-null mice on treatment with the synthetic LXR agonist T0901317 (0.015% dietary supplementation, 10 days), whereas these concentrations were reduced by approximately 75% in wild-type mice. Both cholesterol and phospholipid concentrations in gallbladder bile were decreased, but, unexpectedly, cholesterol/phospholipid ratios were unchanged in the absence of Abcg5 and increased in both genotypes on LXR activation. Hepatic expression of Abcg8 was reduced by about 35% in Abcg5-deficient mice when compared with controls. No compensatory overexpression of other ABC transporters potentially involved in hepatic cholesterol trafficking was observed on messenger RNA level. CONCLUSIONS: Our data show that disruption of the Abcg5 gene alone is sufficient to cause hyperabsorption of dietary plant sterols and sitosterolemia in mice, whereas the ability to secrete cholesterol into bile is maintained.

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