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CD44 is a key player in non-alcoholic steatohepatitis.
- Source :
-
Journal of hepatology [J Hepatol] 2017 Aug; Vol. 67 (2), pp. 328-338. Date of Electronic Publication: 2017 Mar 16. - Publication Year :
- 2017
-
Abstract
- Background & Aims: Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression.<br />Methods: The role of CD44 was evaluated in CD44 <superscript>-/-</superscript> mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n=30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n=64) were evaluated.<br />Results: Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44 <superscript>-/-</superscript> mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p=0.0008) and correlated with NAFLD activity score (NAS) (p=0.001), ballooning (p=0.003), alanine transaminase (p=0.005) and hepatic CCL2 (p<0.001) and macrophage marker CD68 (p<0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44 <superscript>+</superscript> cells. Finally, the soluble form of CD44 increased with severe steatosis (p=0.0005) and NASH (p=0.007).<br />Conclusion: Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH.<br />Lay Summary: Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy.<br /> (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Adult
Animals
Bariatric Surgery
Biomarkers metabolism
Disease Models, Animal
Female
Humans
Hyaluronan Receptors blood
Hyaluronan Receptors deficiency
Hyaluronan Receptors genetics
Liver immunology
Liver metabolism
Liver pathology
Macrophages immunology
Macrophages metabolism
Macrophages pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Non-alcoholic Fatty Liver Disease metabolism
Non-alcoholic Fatty Liver Disease pathology
Obesity, Morbid blood
Obesity, Morbid metabolism
Obesity, Morbid surgery
Up-Regulation
Hyaluronan Receptors metabolism
Non-alcoholic Fatty Liver Disease etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0641
- Volume :
- 67
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 28323124
- Full Text :
- https://doi.org/10.1016/j.jhep.2017.03.003