Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
Chem Biol Drug Des. 2024 May;103(5):e14532. doi: 10.1111/cbdd.14532.
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that causes severe liver damage, fibrosis, and scarring. Despite its potential to progress to cirrhosis or hepatic failure, approved drugs or treatments are currently unavailable. We developed 4,4-diallyl curcumin bis(2,2-hydroxymethyl)propanoate, also known as 35e, which induces upregulation of mitochondrial proteins including carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II, heat shock protein 60, and translocase of the outer mitochondrial membrane 20. Among these proteins, the upregulated expression of CPT-I was most prominent. CPT-I plays a crucial role in transporting carnitine across the mitochondrial inner membrane, thereby initiating mitochondrial β-oxidation of fatty acids. Given recent research showing that CPT-I activation could be a viable pathway for NASH treatment, we hypothesized that 35e could serve as a potential agent for treating NASH. The efficacy of 35e in treating NASH was evaluated in methionine- and choline-deficient (MCD) diet- and Western diet (WD)-induced models that mimic human NASH. In the MCD diet-induced model, both short-term (2 weeks) and long-term (7 weeks) treatment with 35e effectively regulated elevated serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) concentrations and histological inflammation. However, the antisteatotic effect of 35e was obtained only in the short-term treatment group. As a comparative compound in the MCD diet-induced model, curcumin treatment did not produce significant regulatory effects on the liver triglyceride/total cholesterol, serum ALT/AST, or hepatic steatosis. In the WD-induced model, 35e ameliorated hepatic steatosis and hepatic inflammation, while increasing serum AST and hepatic lipid content. A decrease in epididymal adipose tissue weight and serum free fatty acid concentration suggested that 35e may promote lipid metabolism or impede lipid accumulation. Overall, 35e displayed significant antilipid accumulation and antifibrotic effects in the two complementary mice models. The development of new curcumin derivatives with the ability to induce CPT-I upregulation could further underscore their efficacy as anti-NASH agents.
非酒精性脂肪性肝炎（NASH）是一种进展性的非酒精性脂肪性肝病（NAFLD），可导致严重的肝损伤、纤维化和瘢痕形成。尽管它有可能进展为肝硬化或肝衰竭，但目前尚无批准的药物或治疗方法。我们开发了 4,4-二烯丙基姜黄素双（2,2-羟甲基）丙酯，也称为 35e，它可诱导包括肉毒碱棕榈酰转移酶 I（CPT-I）、肉毒碱棕榈酰转移酶 II、热休克蛋白 60 和外膜 20 转位酶在内的线粒体蛋白上调。在这些蛋白质中，CPT-I 的上调表达最为显著。CPT-I 在将肉毒碱转运穿过线粒体内膜中起关键作用，从而启动脂肪酸的线粒体β-氧化。鉴于最近的研究表明 CPT-I 激活可能是治疗 NASH 的可行途径，我们假设 35e 可以作为治疗 NASH 的潜在药物。35e 在蛋氨酸和胆碱缺乏（MCD）饮食和西方饮食（WD）诱导的模型中治疗 NASH 的疗效进行了评估，这些模型模拟了人类 NASH。在 MCD 饮食诱导的模型中，35e 的短期（2 周）和长期（7 周）治疗均有效调节了升高的血清丙氨酸氨基转移酶（ALT）/天冬氨酸氨基转移酶（AST）浓度和组织学炎症。然而，35e 的抗脂肪变性作用仅在短期治疗组中获得。作为 MCD 饮食诱导模型中的比较化合物，姜黄素治疗对肝脏甘油三酯/总胆固醇、血清 ALT/AST 或肝脂肪变性没有产生显著的调节作用。在 WD 诱导的模型中，35e 改善了肝脂肪变性和肝炎症，同时增加了血清 AST 和肝脂质含量。附睾脂肪组织重量和血清游离脂肪酸浓度的降低表明，35e 可能促进脂质代谢或阻止脂质积累。总体而言，35e 在两种互补的小鼠模型中表现出显著的抗脂质积累和抗纤维化作用。开发具有诱导 CPT-I 上调能力的新型姜黄素衍生物可能进一步强调它们作为抗 NASH 药物的疗效。
