Hepatic‐specific Pgc‐1α ablation drives fibrosis in a MASH model

脂肪变性 脂肪性肝炎 内分泌学 纤维化 氧化应激 胰岛素抵抗 内科学 脂肪肝 生物 生物能学 脂质代谢 非酒精性脂肪肝 线粒体 炎症 医学 胰岛素 细胞生物学 疾病
作者
Maria Arconzo,Elena Piccinin,Emanuela Pasculli,Marica Cariello,Nicolas Loiseau,Justine Bertrand‐Michel,Hervé Guillou,Maria Laura Matrella,Gaetano Villani,Antonio Moschetta
出处
期刊:Liver International [Wiley]
卷期号:44 (10): 2738-2752 被引量:1
标识
DOI:10.1111/liv.16052
摘要

Abstract Background & Aims Metabolic dysfunction‐associated steatohepatitis (MASH) is a growing cause of chronic liver disease, characterized by fat accumulation, inflammation and fibrosis, which development depends on mitochondrial dysfunction and oxidative stress. Highly expressed in the liver during fasting, peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC‐1α and steatohepatitis. Methods We measured the hepatic expression of Pgc‐1α in both MASH patients and wild‐type mice fed a western diet (WD) inducing steatosis and fibrosis. We then generated a pure C57BL6/J strain loss of function mouse model in which Pgc‐1α is selectively deleted in the liver and we fed these mice with a WD supplemented with sugar water that accurately mimics human MASH. Results We observed that the hepatic expression of Pgc‐1α is strongly reduced in MASH, in both humans and mice. Moreover, the hepatic ablation of Pgc‐1α promotes a considerable reduction of the hepatic mitochondrial respiratory capacity, setting up a bioenergetic harmful environment for liver diseases. Indeed, the lack of Pgc‐1α decreases mitochondrial function and increases inflammation, fibrosis and oxidative stress in the scenario of MASH. Intriguingly, this profibrotic phenotype is not linked with obesity, insulin resistance and lipid disbalance. Conclusions In a MASH model the hepatic ablation of Pgc‐1α drives fibrosis independently from lipid and glucose metabolism. These results add a novel mechanistic piece to the puzzle of the specific and crucial role of mitochondrial function in MASH development.
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