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Chemokine (C-C motif) ligand 2 gene ablation protects low-density lipoprotein and paraoxonase-1 double deficient mice from liver injury, oxidative stress and inflammation.

Fedra Luciano-Mateo,N. Cabré,S. Fernández-Arroyo,G. Baiges-Gaya,Anna Hernández-Aguilera,Elisabet Rodríguez-Tomàs,Maria Mercado-Gómez,J. Menéndez,J. Camps,J. Joven

Published 2019 in Biochimica et Biophysica Acta - Molecular Basis of Disease

ABSTRACT

The risk of non-alcoholic fatty liver disease increases with obesity. Vulnerability to oxidative stress and/or inflammation represents a crucial step in non-alcoholic fatty liver disease progression through abnormal metabolic responses. In this study, we investigated the role of CCL2 gene ablation in mice that were double deficient in low density lipoprotein receptor and in paraoxonase-1. Mass spectrometry methods were used to assess the liver metabolic response in mice fed either regular chow or a high-fat diet. Dietary fat caused liver steatosis, oxidative stress and the accumulation of pro-inflammatory macrophages in the livers of double deficient mice. We observed alterations in energy metabolism-related pathways and in metabolites associated with the methionine cycle and the glutathione reduction pathway. This metabolic response was associated with impaired autophagy. Conversely, when we established CCL2 deficiency, histologic features of fatty liver disease were abrogated, hepatic liver oxidative stress decreased, and anti-inflammatory macrophage marker expression levels increased. These changes were associated with the normalization of metabolic disturbances and increased lysosome-associated membrane protein 2, expression, which suggests enhanced chaperone-mediated autophagy. This study demonstrates that CCL2 is a key molecule for the development of metabolic and histological alterations in the liver of mice sensitive to the development of hyperlipidemia and hepatic steatosis, a finding with potential to identify new therapeutic targets in liver diseases.

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