FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption

Bile acid malabsorption, which in patients leads to excessive fecal bile acid excretion and diarrhea, is characterized by a vicious cycle in which the feedback regulation of bile acid synthesis is interrupted, resulting in additional bile acid production. Feedback regulation of bile acid synthesis is under the control of an endocrine pathway wherein activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), induces enteric expression of the hormone, fibroblast growth factor 15 (FGF15). In liver, FGF15 acts together with FXR-mediated expression of small heterodimer partner to repress bile acid synthesis. Here, we show that the FXR-FGF15 pathway is disrupted in mice lacking apical ileal bile acid transporter, a model of bile acid malabsorption. Treatment of Asbt-/- mice with either a synthetic FXR agonist or FGF15 downregulates hepatic cholesterol 7alpha-hydroxylase mRNA levels, decreases bile acid pool size, and reduces fecal bile acid excretion. These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption.     

胆汁酸受体FXR 的研究进展

法尼酯衍生物X受体(FXR)是一种胆汁酸受体,在胆汁酸代谢和胆固醇代谢中发挥重要作用,并有望成为降低胆固醇,治疗某些心血管病及肝脏疾病的治疗靶点。本文介绍了FXR的发现、FXR在调控胆汁酸和脂质代谢中的作用,以及FXR在心血管疾病治疗中的应用前景。     

核受体FXR:一种新型代谢调节因子

法尼酯衍生物X受体(farnesoid X receptor,FXR)是一种胆汁酸受体,属于核受体超家族成员。FXR通过调控一系列基因的表达,在胆汁酸、脂质和糖代谢中发挥重要作用,进而有望成为治疗一系列代谢性疾病的药物靶点。本文将就FXR的相关研究进展作一综述。     

Essential roles of bile acids and their nuclear receptors,FXR and PXR,in the cholestatic liver disease

Bile acids (BAs) are steroid acids found predominantly in the bile of mammals and other vertebrates. Though BAs have been known as digestive juice, recent studies have revealed that BAs act as signaling molecules to control metabolism and inflammation. Today, BAs are considered as potential therapeutic molecules for treatment of complex metabolic liver disease. However, the detergent properties of BAs lead to hepatic injury and intrahepatic cholestasis when BAs are accumulated in the liver with impaired bile flow into gall bladder. Cholestasis is a pathological condition of hepatic retention of cytotoxic bile acids. To date, hydrophilic ursodeoxycholic acid has been currently used to treat cholestasis, but the efficacy of UDCA for cholestasis is still limited. Given that BAs are endogenous ligands of several nuclear receptors, including Farnesoid X receptor and Pregnane X receptor, novel synthetic ligands for those nuclear receptors are promising for the treatment of cholestatic liver diseases.     

Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes

Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.     

A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids

Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA). In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR. PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists. In contrast, fibroblast growth factor-19 (FGF-19) mRNA levels were greatly induced by these same FXR agonists. Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased PON1 mRNA levels. Finally, deletion studies revealed that the proximal -230 to -96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19.     

Episodic Molecular Evolution of Pituitary Growth Hormone in Cetartiodactyla

The sequence of growth hormone (GH) is generally strongly conserved in mammals, but episodes of rapid change occurred during the evolution of primates and artiodactyls, when the rate of GH evolution apparently increased substantially. As a result the sequences of higher primate and ruminant GHs differ markedly from sequences of other mammalian GHs. In order to increase knowledge of GH evolution in Cetartiodactyla (Artiodactyla plus Cetacea) we have cloned and characterized GH genes from camel (Camelus dromedarius), hippopotamus (Hippopotamus amphibius), and giraffe (Giraffa camelopardalis), using genomic DNA and a polymerase chain reaction technique. As in other mammals, these GH genes comprise five exons and four introns. Two very similar GH gene sequences (encoding identical proteins) were found in each of hippopotamus and giraffe. The deduced sequence for the mature hippopotamus GH is identical to that of dolphin, in accord with current ideas of a close relationship between Cetacea and Hippopotamidae. The sequence of camel GH is identical to that reported previously for alpaca GH. The sequence of giraffe GH is very similar to that of other ruminants but differs from that of nonruminant cetartiodactyls at about 18 residues. The results demonstrate that the apparent burst of rapid evolution of GH occurred largely after the separation of the line leading to ruminants from other cetartiodactyls.     

Constitutive activity and ligand-dependent activation of the nuclear receptor CAR-insights from molecular dynamics simulations

The constitutive androstane receptor (CAR) possesses, unlike most other nuclear receptors, a pronounced basal activity in vitro whose structural basis is still not fully understood. Using comparative molecular dynamics simulations of CAR X-ray crystal structures, we evaluated the molecular basis for constitutive activity and ligand-dependent receptor activation. Our results suggest that a combination of van der Waals interactions and hydrogen bonds is required to maintain the activation helix in the active conformation also in absence of a ligand. Furthermore, we identified conformational rearrangements within the ligand-binding pocket upon agonist binding and an influence of CAR inducers pregnanedione and CITCO on the helical conformation of the activation helix. Based on the results a model for ligand-dependent CAR activation is suggested.