Xenobiotic receptors

胆汁酸（BA）是来自肝脏中胆固醇的洗涤剂样分子。胆汁酸的主要功能包括：（1）产生胆汁流量，诱导肝脏分泌胆汁脂质（磷脂和胆固醇）;（2）形成胶束，促进营养素的吸收（脂质、胆固醇和脂溶性维生素）;和（3）作为激素通过核和G-蛋白偶联受体发出信号以调节胆汁酸肠肝循环，肝功能，肠道蠕动和能量代谢。除了这些有益的功能之外，BA在肝细胞中的积累触发胆汁淤积性损伤。肝脏BA合成是人体胆固醇代谢的主要途径。在肝脏中合成的BA被称为初级BA（胆酸，CA和鹅去氧胆酸，CDCA），以将它们与由肠道微生物群进行的反应形成的次级BA区分开。初级BA主要通过两种途径合成，经典途径和较小程度的替代途径。经典（或中性）胆汁酸生物合成途径由限速酶胆固醇7 α-羟化酶（CYP 7A 1）启动，产生大部分BA库。在3 β-羟基-d5-C27-类固醇氧化还原酶（HSD 3B 7）作用后，胆汁酸代谢中间体通过固醇12 α-羟化酶（CYP 8B 1）进一步转化为CA，而那些逃避CYP 8B 1作用的中间体通过线粒体固醇27-羟化酶（CYP 27 A1）转化为CDCA。在这种能力下，CYP 8B 1控制CA合成速率，并且是12 α-羟基化（12 α-OH）与非12 α-OH BA比率的重要决定因素。另一种（或酸性）途径由CYP 27 A1启动，随后由氧固醇7 α-羟化酶（CYP 7 B1）作用形成CDCA。在啮齿类动物中，另外两种主要BA α-和β-鼠胆酸（MCA）分别由CDCA和熊去氧胆酸（UDCA）通过CYP 2C 70介导的6-羟基化产生。肝细胞通过直接接触门静脉血浆的窦状膜摄取BA，并在小管膜处将BA排泄到胆汁中;这是BA的肠肝循环中的两个重要步骤。过氧化物酶体增殖物激活受体α（PPARalpha）通过调节脂质转运和catalysts来控制脂质稳态。PPARalpha激活剂在临床上用于高脂血症治疗。PPARalpha在BA稳态中的作用开始显现。本文中，用有效的PPARalpha激动剂Wy-14，643（Wy）处理PPARalpha-无效和肝细胞特异性PPARalpha-无效（PPara-dHep）以及相应的野生型小鼠，并进行总体代谢组学以阐明肝细胞PPARalpha在调节BA稳态中的作用。所有血清BA的水平在Wy-treated野生型小鼠中显著升高，但在Ppara-null和Ppara-dHep小鼠中没有。基因表达分析表明，激活PPARalpha后，（1）降低了负责BA进入肝脏的牛磺胆酸钠转运多肽和有机离子转运多肽1和4的表达，（2）降低了将BA从肝细胞转运到胆小管的胆盐输出泵的表达;（3）上调多药耐药相关蛋白3和4的表达，使BA从肝细胞转运至门静脉。此外，有一个显着的增加，血清，肝脏和胆汁中的胆酸和牛磺胆酸的组成Wy治疗后，这与Cyp 8b 1基因编码的甾醇12 α-羟化酶的表达上调。Wy的作用在Ppara-dHep和Ppara-null小鼠之间是相同的。肝细胞PPARalpha不仅通过直接的转录调控，还通过与肝法尼醇X受体信号转导的相互作用来控制BA的合成和转运。这些发现强调了肝细胞PPARalpha在BA稳态控制中的关键作用。

Bile acids (BAs) are detergent-like molecules derived from cholesterol in the liver. The major functions of BAs include: (1) generating bile flow and inducing hepatic secretion of biliary lipids (phospholipid and cholesterol); (2) forming micelles and facilitating absorption of nutrients (lipids, cholesterol, and fat-soluble vitamins) in the gut; and (3) acting as hormones to signal through nuclear and G-protein-coupled receptors in order to regulate the bile acid enterohepatic circulation, hepatic function, gut motility, and energy metabolism. Besides these beneficial functions, the accumulation of BAs in hepatocytes triggers cholestatic injury. Hepatic BA synthesis is the predominant metabolic pathway for cholesterol catabolism in humans. BAs synthesized in the liver are designated primary BAs (cholic acid, CA, and chenodeoxycholic acid, CDCA) to distinguish them from the secondary BAs that are formed by reactions carried out by the gut microbiota. Primary BAs are mainly synthesized via two pathways, the classic pathway and to a lesser extent the alternative pathway. The classic (or neutral) bile acid biosynthetic pathway is initiated by the rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1), producing most of the BA pool. Following the action of 3beta-hydroxy-d5-C27-steroid oxidoreductase (HSD3B7), a bile acid metabolic intermediate is further converted to CA by sterol 12alpha-hydroxylase (CYP8B1) and those that escape the action of CYP8B1 are transformed to CDCA by mitochondrial sterol 27-hydroxylase (CYP27A1). In this capacity, CYP8B1 controls the rate of CA synthesis and is an important determinant of the ratio of 12alpha-hydroxylated (12alpha-OH) to non-12alpha-OH BAs. An alternative (or acidic) pathway is initiated by CYP27A1, followed by the action of oxysterol 7alpha-hydroxylase (CYP7B1) to form CDCA. In rodents, another two primary BAs alpha- and beta-muricholic acid (MCA) are generated from CDCA and ursodesoxycholic acid (UDCA) via CYP2C70-mediated 6-hydroxylation, respectively. Hepatocytes take up BAs through the sinusoidal membrane which directly contacts the portal blood plasma, and excrete BAs at the canalicular membrane into bile; these are two important steps in the enterohepatic circulation of BAs. Peroxisome proliferator-activated receptor alpha (PPARalpha) controls lipid homeostasis through regulation of lipid transport and catabolism. PPARalpha activators are clinically used for hyperlipidemia treatment. The role of PPARalpha in BA homeostasis is beginning to emerge. Herein, Ppara-null and hepatocyte-specific Ppara-null (Ppara-dHep) as well as the respective wild-type mice were treated with the potent PPARalpha agonist Wy-14,643 (Wy) and global metabolomics performed to clarify the role of hepatocyte PPARalpha in the regulation of BA homeostasis. Levels of all serum BAs were markedly elevated in Wy-treated wild-type mice but not in Ppara-null and Ppara-dHep mice. Gene expression analysis showed that PPARalpha activation (1) down-regulated the expression of sodium-taurocholate acid transporting polypeptide and organic ion transporting polypeptide 1 and 4, responsible for the uptake of BAs into the liver; (2) decreased the expression of bile salt export pump transporting BA from hepatocytes into the bile canaliculus; (3) upregulated the expression of multidrug resistance-associated protein 3 and 4 transporting BA from hepatocytes into the portal vein. Moreover, there was a notable increase in the compositions of serum, hepatic and biliary cholic acid and taurocholic acid following Wy treatment, which correlated with the upregulated expression of the Cyp8b1 gene encoding sterol 12alpha-hydroxylase. The effects of Wy were identical between the Ppara-dHep and Ppara-null mice. Hepatocyte PPARalpha controlled BA synthesis and transport not only via direct transcriptional regulation but also via crosstalk with hepatic farnesoid X receptor signaling. These findings underscore a key role for hepatocyte PPARalpha in the control of BA homeostasis.