Roles of nuclear receptors in the up-regulation of hepatic cholesterol 7alpha-hydroxylase by cholestyramine in rats.
Nuclear receptors are involved in regulating the expression of cholesterol 7alpha-hydroxylase (CYP7A1), however, their roles in the up-regulation of CYP7A1 by cholestyramine (CSR) are still unclear. In the present study, male Wistar rats were divided into four groups and fed [high sucrose + 10% lard diet] (H), [H + 3% CSR diet] (H + CSR), [H + 0.5% cholesterol + 0.25% sodium cholate diet] (C), or [C + 3% CSR diet] (C + CSR) for 2 weeks. Cholestyramine decreased serum and liver cholesterol levels significantly in rats fed C-based diets, but had no effect on these parameters in rats fed H-based diets. Cholestyramine raised hepatic levels of CYP7A1 mRNA and activity in both groups. The gene expression of hepatic ATP-binding cassettes A1 and G5, regulated by liver X receptor (LXR), were unchanged and down-regulated by cholestyramine, respectively. The mRNA levels of the hepatic ATP-binding cassette B11 and short heterodimer partner (SHP), regulated by farnesoid X receptor (FXR), were not changed by cholestyramine. C-based diets, which contained cholesterol and cholic acid, increased SHP mRNA levels compared to H-based diets. Consequently, in rats fed the C+CSR diet, hepatic FXR was activated by dietary bile acids, but the hepatic CYP7A1 mRNA level was increased 16-fold compared to that in rats fed an H diet. These results suggest that cholestyramine up-regulates the expression of CYP7A1 independently via LXR- or FXR-mediated pathways in rats.
Shibata
Shinya
S
Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi, Tokyo 186-8650, Japan. shinya-shibata@yakult.co.jp
Hayakawa
Kazuhito
K
Egashira
Yukari
Y
Sanada
Hiroo
H
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D002792:Cholestyramine Resin / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006937:Hypercholesterolemia / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000924:Anticholesteremic Agents; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D002792:Cholestyramine Resin; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase