PDF(Pubmed)
Abstract：
Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5\'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.
摘要：
胆汁淤积性肝病,包括原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC），由于胆汁流动受损，导致胆汁酸的肝脏滞留，导致肝损伤。直到最近,唯一批准的PBC治疗是熊去氧胆酸(UDCA)和奥贝胆酸(OCA).虽然这些疗法在疾病的早期阶段减缓了PBC的进展，大约40%的患者对UDCA反应不完全，先进的案例没有回应。UDCA不能改善PSC患者的生存率，并且患者通常对OCA有剂量限制性瘙痒反应。未经治疗，这些疾病可以进展为纤维化和肝硬化，导致肝功能衰竭和需要移植。这些缺点强调迫切需要替代治疗策略。最近,核激素受体已被探索作为辅助治疗的药理学靶标，因为它们调节参与胆汁酸代谢和解毒的酶。特别是,过氧化物酶体增殖物激活受体(PPAR)已成为对UDCA反应不完全的PBC或PSC患者的治疗靶点.PPARα主要在肝脏中表达，它在细胞色素P450（CYP）和尿苷5'-二磷酸-葡萄糖醛酸基转移酶（UGT）酶的调节中起着至关重要的作用，这两个都是关键的酶家族参与胆汁酸代谢和葡萄糖醛酸化的调节，分别。重要的是,PPARα激动剂,例如，非诺贝特,在减少PBC和PSC患者胆汁淤积标志物升高方面显示出治疗益处，还有Elafibranor,第一个PPAR(双α，β/δ)激动剂，已被FDA批准用于PBC的二线治疗。此外,靶向各种PPAR亚型的新型PPAR激动剂(β/δ，γ)正在开发中作为PBC或PSC的辅助疗法，尽管它们对葡糖醛酸化途径的影响较少。这篇综述将集中于PPAR介导的胆汁酸葡糖醛酸化作为改善PBC和PSC患者预后的治疗途径。
