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

Autor: Arconzo M; Department of Interdisciplinary Medicine (DIM), University of Bari 'Aldo Moro', Bari, Italy., Piccinin E; Department of Interdisciplinary Medicine (DIM), University of Bari 'Aldo Moro', Bari, Italy.; Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari 'Aldo Moro', Bari, Italy., Pasculli E; Department of Interdisciplinary Medicine (DIM), University of Bari 'Aldo Moro', Bari, Italy., Cariello M; Department of Interdisciplinary Medicine (DIM), University of Bari 'Aldo Moro', Bari, Italy., Loiseau N; Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France., Bertrand-Michel J; MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France., Guillou H; Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France., Matrella ML; Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari 'Aldo Moro', Bari, Italy., Villani G; Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari 'Aldo Moro', Bari, Italy., Moschetta A; Department of Interdisciplinary Medicine (DIM), University of Bari 'Aldo Moro', Bari, Italy.; INBB, National Institute for Biostructures and Biosystems, Rome, Italy.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2024 Oct; Vol. 44 (10), pp. 2738-2752. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1111/liv.16052
Abstrakt: 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.
(© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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