Xenobiotic receptors

胆汁酸(BAs)是一种类似洗涤剂的分子，源自肝脏中的胆固醇。BAS的主要功能包括：(1)产生胆汁流动，诱导肝脏分泌胆汁脂类(磷脂和胆固醇)；(2)在肠道形成胶束，促进营养物质(脂类、胆固醇和脂溶维生素)的吸收；(3)作为激素，通过核受体和G蛋白偶联受体发出信号，调节胆汁酸的肝-肠循环、肝功能、肠道运动和能量代谢。除了这些有益的功能外，bas在肝细胞中的积聚还会触发胆汁淤积性损伤。肝脏BA合成是人体胆固醇分解代谢的主要代谢途径。在肝脏中合成的BAs被命名为初级BAs(胆酸，CA，和鹅去氧胆酸，CDCA)，以区别于由肠道微生物区系进行反应而形成的次级BAs。初级BA主要通过两条途径合成，经典途径和次要途径。经典的(或中性的)胆汁酸生物合成途径是由限速酶胆固醇7α-羟基酶(CyP7A1)启动的，产生大部分BA池。在3β-羟基-d5-C27-类固醇氧化还原酶(HSD3B7)的作用下，胆汁酸代谢中间体进一步被甾醇12α-羟基酶(CYP8B1)转化为CA，而逃脱CYP8B1作用的中间产物则通过线粒体固醇27-羟基酶(CYP27A1)转化为CDCA。在这一能力中，CYP8B1控制CA的合成速度，是12α-羟化(12α-OH)与非12α-OH bas比率的重要决定因素。另一条(或酸性的)途径是由CYP27A1启动的，随后是氧固醇7α-羟基酶(CyP7B1)的作用，形成CDCA。在啮齿类动物中，CDCA和熊去氧胆酸(UDCA)分别通过CYP2C70介导的6-羟基化反应生成另外两种基本的α-和β-鼠李酸(MCA)。肝细胞通过与门静脉血浆直接接触的肝窦膜摄取BAS，并在肝小管膜处将BAS排泄到胆汁中，这是BAS肠-肝循环的两个重要步骤。过氧化物酶体增殖物激活受体α(PPARpha)通过调节脂质转运和分解代谢来控制脂质的动态平衡。PPARpha激活剂是临床上用于治疗高脂血症的药物。PPARpha在BA动态平衡中的作用开始显现。在此，我们用有效的PPARα激动剂Wy-14,643(Wy)和全局代谢组学方法，对Ppara阴性小鼠和肝细胞特异性Ppara阴性小鼠(PpardHep)以及相应的野生型小鼠进行治疗，以阐明肝细胞PPARpha在BA稳态调节中的作用。WY治疗的野生型小鼠的所有血清bas水平显著升高，但在Pparnull和PpardHep小鼠中则没有。基因表达分析表明，PPARpha激活(1)下调负责BAS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)降低将BA从肝细胞输送到胆小管的胆盐输出泵的表达；(3)上调从肝细胞向门静脉输送BA的多药耐药相关蛋白3和4的表达。此外，WY治疗后血清、肝脏和胆汁中胆酸和牛磺胆酸的组成显著增加，这与编码甾醇12α-羟基酶的Cyp8b1基因表达上调有关。WY在Ppara-dHep小鼠和Ppara-null小鼠之间的作用是相同的。肝细胞PPARpha不仅通过直接转录调节调控BA的合成和转运，而且还通过与肝法尼醇X受体信号的串扰来控制BA的合成和运输。这些发现强调了肝细胞PPARpha在BA动态平衡控制中的关键作用。

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.