β7-Integrins and MAdCAM-1 play an opposing role during the development of Non-alcoholic steatohepatitis (NASH)

Abstract

Introduction: Non-alcoholic steatohepatitis (NASH), the hepatic correlate of the metabolic syndrome, is the third most common cause of chronic liver disease in western countries. Its global incidence is on the rise and reflects one of the fastest growing medical problems. Aim: The significance of leukocyte infiltration during the development of NASH remains unclear until now. We therefore investigated the role of β7-Integrin and one of its receptors MAdCAM-1 in a mouse model of NASH development. Methods: Constitutive MAdCAM-1 and β7-Integrin knockout (KO) mice were fed a MCD diet (methionine and choline deficient) for 4 weeks. Results: Interestingly β7-deficient mice displayed an earlier and faster progressing steatohepatitis during MCD treatment, while MAdCAM-1 KO showed less histomorphological changes in contrast to wildtype mice. Oxidative stress analysis in β7 KO mice showed a stronger response as indicated by DHE (dihydroethidium) staining and a down regulation of transcription factors involved in anti-oxidative stress and fatty acid metabolism (e.g. FAS and SREBP). MAdCAM-1 KO mice on the other hand had an upregulation of the anti-oxidative stress response. Moreover, we detected a stronger hepatic infiltration of inflammatory cells (CD4+ and CD11b+) in the β7 KO group, reflecting an earlier onset of NASH. Those changes finally resulted in an earlier and stronger collagen accumulation (Sirius red) in the β7-Integrin deficient group, while MAdCAM-1 KO mice were protected. Conclusion: MAdCAM-1 and β7 Integrins mediate opposing effects in the MCD model, with protection in MAdCAM-1 KO animals and a more severe phenotype and significantly stronger fibrosis progression in β7-Integrin KO mice. Therefore, the interaction of β7 Integrins and their receptor MAdCAM-1 provide a novel interesting target for therapeutic interventions during NASH development.