| AimsObesity induced by high-energy food diet is a burgeoning health problem worldwide and one of the high-risk factors for lipids metabolic disorders.Importantly,cholesterol accumulation in the body under obesity condition is one of the common pathogenic factors associated with the relevant diseases.However,cholesterol levels in liver exhibit discrepancy at different stages of the high-fat diet(HFD)-induced obesity,which exhibit hepatic cholesterol accumulation and restoration,but the corresponding mechanisms remain unclear.Bile acids(BAs)as the critical endogenous ligands of farnesoid X receptor(Fxr)have been demonstrated that they can regulate the relevant enzymes and transporters at transcriptional level to determine the cholesterol homeostasis in vivo.Here,we preliminary explored the molecular mechanisms of hepatic cholesterol accumulation and restoration via the BAs-Fxr signaling pathway and its downstream enzymes and transporters under the different stages of the HFD-induced obesity in rats.Moreover,the alterations of the rosuvastatin pharmacokinetics in the obese rats were also studied.Based on the findings,it is expected to provide a basis for clinical treatment and rational use of drugs for obese patients with cholesterol disorder.MethodsFour-week-old male Wistar rats(body weight 80±20 g)were fed with HFD and normal diet for 4 and 8 weeks,respectively.At the experiment day,the abdominal aorta blood,liver,ileum and abdominal fat samples were collected.After the samples were processed by the corresponding methods,the cholesterol levels in the serum,liver and ileum tissues,the concentrations of total BAs and individual BAs in liver and ileum tissues,the pathological changes in liver and abdominal adipose tissue,and the mRNA expressions of enzymes,transporters and nuclear receptors involving in physiological homeostasis of cholesterol and BAs in liver and ileum tissue were analyzed.In addition,the pharmacokinetics and primary hepatocyte uptake of rosuvastatin in rats with HFD-induced obesity for 4 weeks were investigated.Results(1)In rat with 4 weeks of HFD induction,the passive diffusion of ileal BAs was promoted by HFD,which led to the BAs levels in ileum tissue increase,especially the levels of the chenodeoxycholic acids(CDCAs)that are the potent agonists of Fxr increased significantly.As a result,the increased concentrations of BAs especially the CDCAs activated the Fxr-fibroblast growth factor 15(Fgf15)pathway in ileum,which resulted in the down-regulation of the hepatic cholesterol 7 alpha-hydroxylase(Cyp7a1)mRNA expression and inhibited the elimination of cholesterol metabolism in liver,ultimately led to the cholesterol accumulation in liver.(2)In rat with 8 weeks of HFD induction,the level of taurine-β-muricholic acid(Tβ-MCA),an Fxr antagonist,in the liver tissue of rats was significantly increased,and it could cause the mRNA expression of hepatic sterol 12 alpha-hydroxylase(Cyp8b1)down-regulation via inhibiting the Fxr-small heterodimer partner(Shp)pathway in liver and then promoted the cholesterol converting into BAs.Meanwhile,the ileal Fxr-ATP-binding cassette transporter superfamily G5(Abcg5)pathway was further activated by the elevated CDCAs levels,and the Abcg5 gene expression was significantly up-regulated,and it could result in the intestinal absorption of cholesterol decreasing.Generally,the up-regulation of hepatic Cyp8b1 and ileum Abcg5 synergistically improved and restored the intrahepatic cholesterol accumulation when compared to that in 4-week obese rats.(3)In 4 weeks HFD-induced obese rats,the hepatic mRNA expression of anion-transporting polypeptide 2(Oatp2)down-regulated significantly,and the concentration of Glycochenodeoxycholate-3-sulfate(GCDCA-S)as the specificity endogenous substrate of Oatp2 in serum decreased profoundly,which led to a decrease in hepatic uptake of rosuvastatin that is the substrate drug of Oatp2,and ultimately resulted in the blood concentration of rosuvastatin increasing.ConclusionAt different stages of HFD-induced obesity in rats,the adaptive alterations of the concentrations and compositions of BAs in liver and ileum tissues regulated the gene expressions of the enzymes and transporters involving in cholesterol homeostasis via the Fxr-mediated signaling pathway,which,ultimately mediated the cholesterol accumulation and the alleviation of cholesterol accumulation in liver.In details,the hepatic cholesterol accumulation in 4-week HFD-induced obesity rats was mainly associated with the inhibition of hepatic Cyp7a1 gene expression,and the hepatic cholesterol accumulation alleviated in 8-week HFD-induced obesity rats could be ascribed to the up-regulation of the gene expressions of the hepatic Cyp8b1 and ileum Abcg5.Futhermore,the down-regulation of mRNA expression of Oatp2 in liver resulted in the increased concentration of rosuvastatin in serum,which may increase the incidence of the adverse reactions of rosuvastatin.Based on the findings from the present study,it is expected to provide a reference for the prevention and treatment of cholesterol disorders and the rational use of rosuvastatin for the obese patients in clinic. |
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