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

Abstract

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.

Peroxisome proliferator-activated receptor α (PPARα) activators induce hepatic farnesyl diphosphate synthase gene expression in rodents

“…Fibrate-induced FPP synthase gene expression has also been observed in the liver of mice treated with 2-diethylhexylphalate (DEHP), another peroxisome proliferator [43]. In addition, it was shown to be correlated with increased HMG-CoA reductase activity or cholesterol synthesis in liver of gemfibrozil-treated rats [23][24][25] and of bezafibrate-treated patients [30]. The opposite effects reported in the same species, as discussed earlier, stem probably from differences between experimental approaches in vivo and in vitro, particularly the dissimilarities in the potency of fibrates, drug dosages and treatment lengths.…”

“…Alternatively, the fibrate analog gemfibrozil can stimulate hepatic HMG-CoA reductase activity or cholesterol synthesis in rats [23][24][25], whereas opposite effects or no effects were observed in response to clofibrate, bezafibrate and WY-14,643 [26][27][28][29]. In humans, hepatic HMG-CoA reductase activity was increased in bezafibrate-treated patients suffering from gallstones [30] whereas bezafibrate or gemfibrozil appeared to inhibit cholesterol synthesis or HMG-CoA reductase activity in mononuclear cells [31,32]. Hence, there is some confusion in this area with positive or negative effects of PPAR␣ ligands on HMG-CoA reductase activity and cholesterogenesis, probably depending on species and fibrate treatment conditions.…”

Therapeutic Effects of Fibrates in Postprandial Lipemia

“…Adverse Effects of Fibrates hyperhomocysteinemia in coronary patients, independently of conventional confounders such as age, gender, smoking, folate and Fibrates have been shown to increase biliary cholesterol secrecyanocobalmain (vitamin B 12) concentrations, serum creatinine tion and decrease bile acid output in humans. [69][70][71] This leads to level, and methylenetetrahydrofolate reductase genotypes. [92] supersaturation of gall bladder bile; an increased incidence of Dierkes et al [93] observed that fenofibrate and bezafibrate led to a cholesterol gallstones have been reported in individuals treated 20-40% elevation of plasma levels of the atherogenic amino acid with fibrates for a prolonged period of time.…”

“…[92] supersaturation of gall bladder bile; an increased incidence of Dierkes et al [93] observed that fenofibrate and bezafibrate led to a cholesterol gallstones have been reported in individuals treated 20-40% elevation of plasma levels of the atherogenic amino acid with fibrates for a prolonged period of time. [70,[72][73][74][75] The adminishomocysteine, thereby possibly counteracting the desired cardiotration of fibrates rarely leads to an increase in the levels of hepatic vascular protection. The most likely mechanism for this increase is transaminases.…”

“…Humans and animals treated with fibrates [70,[148][149][150] teins. Specifically, the immunoaffinity gels absorb apo B100 and display a decrease in the enzyme activity of cholesterol 7-hydrox-AI containing lipoproteins (LDL, nascent VLDL, HDL, and ylase.…”