1. Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis
- Author
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Irene Locatelli, Francesco Vizzutti, N. Navari, Emanuele Albano, Alessandra Caligiuri, Erica Novo, Maurizio Parola, Massimo Pinzani, W. Delogu, E. Zamara, Fabio Marra, Salvatore Sutti, S. Galastri, E. Vivoli, A. Provenzano, and Stefano Milani
- Subjects
Liver Cirrhosis ,HNE, 4-hydroxynonenal, IFN-γ, interferon-γ ,Adipose tissue ,AST, aspartate aminotransferase ,iNOS, inducible NO synthase ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,CC chemokine ligand 2 ,Fibrosis ,Transforming Growth Factor beta ,cytokine ,Chemokine CCL2 ,liver fibrosis ,Mice, Knockout ,0303 health sciences ,TIMP-1, tissue inhibitor of metalloproteinases-1 ,Mice, Inbred BALB C ,Fatty liver ,CCL2, CC chemokine ligand 2 ,General Medicine ,MGL1, macrophage galactose-type C-type lectin 1 ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,TNFα, tumour necrosis factor α ,030211 gastroenterology & hepatology ,non-alcoholic steatohepatitis ,Research Article ,medicine.medical_specialty ,NAFLD, non-alcoholic fatty liver disease ,ALT, alanine transaminase ,NASH, non-alcoholic steatohepatitis ,Biology ,S2 ,Collagen Type I ,03 medical and health sciences ,ROS, reactive oxygen species ,Species Specificity ,Internal medicine ,TGF-β, transforming growth factor-β ,medicine ,Hepatic Stellate Cells ,Animals ,Sirius Red ,030304 developmental biology ,KO, knockout ,Tissue Inhibitor of Metalloproteinase-1 ,Macrophages ,chemokine ,medicine.disease ,WT, wild-type ,Dietary Fats ,IL, interleukin ,Fatty Liver ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,chemistry ,Alanine transaminase ,Immunology ,CCR2, CC chemokine receptor 2 ,Hepatic stellate cell ,biology.protein ,Steatosis ,Steatohepatitis ,RT, real-time ,FAM, 6-carboxyfluorescein ,MCD diet, methionine/choline-deficient diet - Abstract
Expression of CCL2 (CC chemokine ligand 2) (or monocyte chemoattractant protein-1) regulates inflammatory cell infiltration in the liver and adipose tissue, favouring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In the present study, we investigated the development of non-alcoholic steatohepatitis induced by an MCD diet (methionine/choline-deficient diet) in mice lacking the CCL2 gene on two different genetic backgrounds, namely Balb/C and C57/Bl6J. WT (wild-type) and CCL2-KO (knockout) mice were fed on a lipid-enriched MCD diet or a control diet for 8 weeks. In Balb/C mice fed on the MCD diet, a lack of CCL2 was associated with lower ALT (alanine transaminase) levels and reduced infiltration of inflammatory cells, together with a lower generation of oxidative-stress-related products. Sirius Red staining demonstrated pericellular fibrosis in zone 3, and image analysis showed a significantly lower matrix accumulation in CCL2-KO mice. This was associated with reduced hepatic expression of TGF-β (transforming growth factor-β), type I procollagen, TIMP-1 (tissue inhibitor of metalloproteinases-1) and α-smooth muscle actin. In contrast, in mice on a C57Bl/6 background, neither ALT levels nor inflammation or fibrosis were significantly different comparing WT and CCL2-KO animals fed on an MCD diet. In agreement, genes related to fibrogenesis were expressed to comparable levels in the two groups of animals. Comparison of the expression of several genes involved in inflammation and repair demonstrated that IL (interleukin)-4 and the M2 marker MGL-1 (macrophage galactose-type C-type lectin 1) were differentially expressed in Balb/C and C57Bl/6 mice. No significant differences in the degree of steatosis were observed in all groups of mice fed on the MCD diet. We conclude that, in experimental murine steatohepatitis, the effects of CCL2 deficiency are markedly dependent on the genetic background.
- Published
- 2012