Pirfenidone prevents and reverses hepatic insulin resistance and steatohepatitis by polarizing M2 macrophages
Pirfenidone prevents and reverses hepatic insulin resistance and steatohepatitis by polarizing M2 macrophages
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DOI：
10.1038/s41374-019-0255-4
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发表时间：
2019-09-01
影响因子：
5
通讯作者：
Ota, Tsuguhito
中科院分区：
文献类型：
--
作者：
Chen, Guanliang;Ni, Yinhua;Ota, Tsuguhito
非酒精性脂肪性肝炎（NASH）与脂毒性肝损伤相关，可导致胰岛素抵抗、炎症和纤维化。尽管NASH的全球发病率有所增加，但目前有希望的治疗方法却很少。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细胞和巨噬细胞的肺内流。在这里，我们研究了吡非尼酮在高胆固醇和高脂肪饮食引起的脂肪毒性NASH小鼠模型中的作用。饲喂12周后，吡非尼酮通过降低脂肪生成和脂肪酸合成相关基因的表达，增强脂肪酸氧化相关基因的表达，减轻了肝脏过度脂质积累和过氧化。流式细胞术显示吡非尼酮可减少肝巨噬细胞总数，特别是CD11c(+)CD206(-)（M1）型巨噬细胞，增加CD11c(-)CD206(+)（M2）型巨噬细胞数量，进而减少t细胞数量，有助于改善胰岛素抵抗和脂肪性肝炎。此外，吡非尼酮在RAW264.7巨噬细胞中以剂量依赖性的方式下调脂多糖（LPS）诱导的M1标记基因mRNA表达，上调il -4诱导的M2标记基因mRNA表达。重要的是，吡非尼酮可以逆转已有NASH小鼠的胰岛素抵抗、肝脏炎症和纤维化。这些发现表明吡非尼酮是治疗NASH的潜在候选药物。
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 CD11c(+)CD206(-)(M1)-type macrophages, increased the number of CD11c(-)CD206(+)(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.