Advanced Preventive Medical Sciences Research Center, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, 920-8640, Japan.
Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan.
Lab Invest. 2019 Sep;99(9):1335-1348. doi: 10.1038/s41374-019-0255-4. Epub 2019 Apr 24.
Nonalcoholic steatohepatitis (NASH) is associated with lipotoxic liver injury, leading to insulin resistance, inflammation, and fibrosis. Despite its increased global incidence, very few promising treatments for NASH are available. Pirfenidone is an antifibrotic agent used to treat pulmonary fibrosis; it suppresses the pulmonary influx of T cells and macrophages. Here, we investigated the effect of pirfenidone in a mouse model of lipotoxicity-induced NASH via a high-cholesterol and high-fat diet. After 12 weeks of feeding, pirfenidone administration attenuated excessive hepatic lipid accumulation and peroxidation by reducing the expression of genes related to lipogenesis and fatty acid synthesis and enhancing the expression of those related to fatty acid oxidation. Flow cytometry indicated that pirfenidone reduced the number of total hepatic macrophages, particularly CD11cCD206(M1)-type macrophages, increased the number of CD11cCD206(M2)-type macrophages, and subsequently reduced T-cell numbers, which helped improve insulin resistance and steatohepatitis. Moreover, pirfenidone downregulated the lipopolysaccharide (LPS)-induced mRNA expression of M1 marker genes and upregulated IL-4-induced M2 marker genes in a dose-dependent manner in RAW264.7 macrophages. Importantly, pirfenidone reversed insulin resistance, hepatic inflammation, and fibrosis in mice with pre-existing NASH. These findings suggest that pirfenidone is a potential candidate for the treatment of NASH.
非酒精性脂肪性肝炎（NASH）与脂毒性肝损伤有关，导致胰岛素抵抗、炎症和纤维化。尽管其全球发病率增加，但可用的 NASH 治疗方法非常有限。吡非尼酮是一种用于治疗肺纤维化的抗纤维化药物；它抑制 T 细胞和巨噬细胞向肺部的浸润。在这里，我们通过高胆固醇和高脂肪饮食研究了吡非尼酮在脂毒性诱导的 NASH 小鼠模型中的作用。在 12 周的喂养后，吡非尼酮通过降低与脂质生成和脂肪酸合成相关的基因的表达，增强与脂肪酸氧化相关的基因的表达，减轻了过量的肝脂质积累和过氧化。流式细胞术表明，吡非尼酮减少了总肝巨噬细胞的数量，特别是 CD11cCD206（M1）型巨噬细胞，增加了 CD11cCD206（M2）型巨噬细胞的数量，随后减少了 T 细胞的数量，有助于改善胰岛素抵抗和脂肪性肝炎。此外，吡非尼酮以剂量依赖性方式下调了 RAW264.7 巨噬细胞中 LPS 诱导的 M1 标记基因的 mRNA 表达，并上调了 IL-4 诱导的 M2 标记基因的表达。重要的是，吡非尼酮逆转了患有预先存在的 NASH 的小鼠的胰岛素抵抗、肝炎症和纤维化。这些发现表明，吡非尼酮是治疗 NASH 的潜在候选药物。
