Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan.
Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Corporation, Saitama, Japan.
Sci Rep. 2020 Nov 11;10(1):19578. doi: 10.1038/s41598-020-75805-z.
We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient L-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.
我们探讨了过氧化物酶体增殖物激活受体α（PPARα）激动剂 GW7647 和抗糖尿病药物二甲双胍对啮齿动物晚期非酒精性脂肪性肝炎（NASH）模型的有益作用，并研究了可能涉及的机制。给小鼠喂食对照饲料或含有 45%脂肪的胆碱缺乏 L-氨基酸定义饮食（HF-CDAA）。用 HF-CDAA 饮食喂养 16 周的小鼠分为四组：未治疗（HF-CDAA）、含有 1000mg/kg 二甲双胍的 HF-CDAA、含有 10mg/kg GW7647 的 HF-CDAA 和含有二甲双胍和 GW7647 的 HF-CDAA 组。单独使用二甲双胍会轻微恶化天冬氨酸和丙氨酸氨基转移酶（AST/ALT）值，而 GW7647 和二甲双胍联合治疗通过激活 AMP 激活蛋白激酶（AMPK）通路极大地抑制了肝损伤和纤维化。进一步的研究表明，联合治疗降低了炎症、纤维化和内质网（ER）应激相关基因的表达，增加了氧化型烟酰胺腺嘌呤二核苷酸（NAD）/还原型烟酰胺腺嘌呤二核苷酸（NADH）比值，表明由于线粒体功能的恢复，联合治疗具有优越性。首次证明了 PPARα 激动剂和二甲双胍在 HF-CDAA 饮食诱导的晚期 NASH 模型中的附加益处，可能是通过恢复线粒体功能和 AMPK 激活，最终抑制肝炎症、内质网应激，然后抑制纤维化。
