Fibrates and cholestasis.
Fibrates and cholestasis.
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DOI：
10.1002/hep.27744
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Boyer JL
中科院分区：
文献类型：
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作者：
Ghonem NS;Assis DN;Boyer JL
胆汁淤积，包括原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC），是胆汁生成受损或中断的结果，并导致包括胆汁盐在内的有毒胆汁成分在细胞内滞留。如果不及时治疗，胆汁淤积会导致肝纤维化和肝硬化，最终导致肝功能衰竭，需要肝移植。目前，这些患者的唯一治疗选择是熊去氧胆酸（UDCA），它可以减缓PBC的进展，特别是在疾病的I期和II期。然而，一些患者对UDCA治疗有不完全反应，而其他更晚期的病例通常仍无反应。对于PSC， UDCA治疗不能提高生存率，其使用建议仍存在争议。这些考虑强调了替代疗法的必要性。肝转运蛋白位于肝细胞的基底外侧（窦状）和根尖（管状）膜上，是胆汁形成和分泌的重要决定因素。核受体在这些肝脏转运体的调节中起着关键作用，是治疗胆汁淤积性肝病的天然靶点。其中一种核受体是过氧化物酶体增殖激活受体α (PPARα)，它通过调节人类胆胆酸合成和运输的基因，包括细胞色素P450 （CYP）异构体7A1 （CYP7A1）、CYP27A1、CYP8B1、UGT1A1、1A3、1A4、1A6、SULT2A1、MDR3和ASBT，在维持胆固醇、脂质和胆胆酸稳态中起核心作用。许多这些基因的表达在胆汁淤积性肝病中发生改变，但很少被广泛研究或确定PPARα作用的机制。在这篇综述中，我们研究了已知的这些机制，并考虑了PPARα配体治疗各种胆汁淤积性肝脏疾病的基本原理。
Cholestasis, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), results from an impairment or disruption of bile production and causes intracellular retention of toxic bile constituents, including bile salts. If left untreated, cholestasis leads to liver fibrosis and cirrhosis, which eventually results in liver failure and the need for liver transplantation. Currently, the only therapeutic option available for these patients is ursodeoxycholic acid (UDCA), which slows the progression of PBC, particularly in stage I and II of the disease. However some patients have an incomplete response to UDCA therapy, while other more advanced cases often remain unresponsive. For PSC, UDCA therapy does not improve survival, and recommendations for its use remains controversial. These considerations emphasize the need for alternative therapies. Hepatic transporters, located along basolateral (sinusoidal) and apical (canalicular) membranes of hepatocytes, are integral determinants of bile formation and secretion. Nuclear receptors are critically involved in the regulation of these hepatic transporters and are natural targets for therapy of cholestatic liver diseases. One of these nuclear receptors is peroxisome proliferator-activated receptor alpha (PPARα) which plays a central role in maintaining cholesterol, lipid and bile acid homeostasis by regulating genes responsible for bile acid synthesis, and transport in humans, including Cytochrome P450 (CYP) isoform 7A1 (CYP7A1), CYP27A1, CYP8B1, UGT1A1, 1A3, 1A4, 1A6, SULT2A1, MDR3, and ASBT. The expression of many of these genes is altered in cholestatic liver diseases but few have been extensively studied or had the mechanism of PPARα effect identified. In this review we examine what is known about these mechanisms and consider the rationale for the use of PPARα ligand therapy in various cholestatic liver disorders.