Effects of clofibrate on some microsomal hydroxylations involved in the formation and metabolism of bile acids in rat liver

Angelin, Bo; Björkhem, Ingemar; Einarsson, Kurt

doi:10.1042/bj1560445

Cited by 18 publications

(2 citation statements)

References 28 publications

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“…In contrast, some studies in rodents did not show an effect on cholesterol 7␣-hydroxylase on fibrate treatment. 19,21 Recently, divergent data on the effect of PPAR␣ agonists on cholesterol 7␣-hydroxylase transcription in promoter-reporter studies have been described. 22,23 The mechanism of action and the potential role of PPAR␣ in the downregulation of cholesterol 7␣-hydroxylase by fibrates remain to be clarified.…”

mentioning

confidence: 99%

Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression

Post¹,

Duez²,

Gervois³

et al. 2001

ATVB

194

124

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Abstract-Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPAR␣ agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7␣-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7␣-hydroxylase enzyme activity and mRNA. The functional involvement of PPAR␣ in the suppression of both enzymes was proven with the use of PPAR␣-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7␣-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (Ϫ45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPAR␣-null mice. A decreased bile acid production by PPAR␣-mediated downregulation of cholesterol 7␣-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.

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mentioning

confidence: 99%

Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression

Post¹,

Duez²,

Gervois³

et al. 2001

ATVB

194

124

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“…Sterol 12␣-hydroxylase is highly regulated, and many of the early studies carried out were involved in the regulation of the enzyme activity. Clofibrate treatment increases sterol 12␣-hydroxylase activity and mRNA level in rat liver microsomes (14,15). The enzyme was initially purified from rabbit liver microsomes by Ishida et al in 1992 (16), and the activity was shown to be elevated by several treatments, including starvation and administration of streptozotocin in rat.…”

mentioning

confidence: 99%

The Peroxisome Proliferator-activated Receptor α (PPARα) Regulates Bile Acid Biosynthesis

Hunt

Yang²,

Eggertsen³

et al. 2000

Journal of Biological Chemistry

148

106

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Fibrates are a group of hypolipidemic agents that efficiently lower serum triglyceride levels by affecting the expression of many genes involved in lipid metabolism. These effects are exerted via the peroxisome proliferator-activated receptor ␣ (PPAR␣). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPAR␣ and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12␣-hydroxylase is a branch-point enzyme in the bile acid biosynthetic pathway, which determines the ratio of cholic acid to chenodeoxycholic acid. Treatment of mice for 1 week with the peroxisome proliferator WY-14,643 or fasting for 24 h both induced the sterol 12␣-hydroxylase mRNA in liver. Using the PPAR␣ knockout mouse model, we show that the induction by both treatments was dependent on the PPAR␣. A reporter plasmid containing a putative peroxisome proliferator-response element (PPRE) identified in the rat sterol 12␣-hydroxylase promoter region was activated by treatment with WY-14,643 in HepG2 cells, being dependent on co-transfection with a PPAR␣ expression plasmid. The rat 12␣-hydroxylase PPRE bound in vitro translated PPAR␣ and retinoid X receptor ␣, albeit weakly, in electrophoretic mobility shift assay. Treatment of wild-type mice with WY-14,643 for 1 week resulted in an increased relative amount of cholic acid, an effect that was abolished in the PPAR␣ null mice, verifying the functionality of the PPRE in vivo.Fibrates and their derivatives constitute a group of hypolipidemic agents that are used in the treatment of hypertriglyceridemia and combined hyperlipidemia. These fibrates belong to a structurally diverse group of compounds known as peroxisome proliferators, which have been shown to cause liver hepatomegaly, proliferation of peroxisomes, and induction of many enzymes involved in peroxisomal and mitochondrial ␤-oxidation and -oxidation of fatty acids (for review, see Ref.

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Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: Reduced activity of cholesterol 7α-hydroxylase

et al. 1995

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Bezafibrate is a hypolipidemic fibric acid derivative known to induce cholesterol supersaturation of bile. To characterize its effects on hepatic cholesterol metabolism, 31 normolipidemic, normal-weight patients with gallstones undergoing cholecystectomy were studied. Eleven patients (5 men) were randomized to treatment with bezafibrate, 200 mg three times daily for 4 weeks before operation; the remaining 20 patients (5 men) served as nontreatment controls. At operation, a liver biopsy specimen was obtained under standardized conditions and several important parameters of cholesterol metabolism were assayed. Bezafibrate treatment lowered total plasma cholesterol and triglycerides 30% and 37%, respectively. The hepatic cholesterol 7 alpha-hydroxylase activity was reduced by approximately 60% in the bezafibrate treated patients compared with the controls, whereas the acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was similar in the two groups. The total 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity was increased twofold in the treated patients, whereas the active enzyme remained about the same as in the controls. The low-density lipoprotein (LDL) receptor binding activity was unaffected by the treatment. Bezafibrate treatment significantly reduces cholesterol 7 alpha-hydroxylase activity, and it is suggested that this may play an important role for the development of supersaturated bile during such therapy.

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Effects of clofibrate on some microsomal hydroxylations involved in the formation and metabolism of bile acids in rat liver

Cited by 18 publications

References 28 publications

Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression

Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression

The Peroxisome Proliferator-activated Receptor α (PPARα) Regulates Bile Acid Biosynthesis

Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: Reduced activity of cholesterol 7α-hydroxylase

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