Therapeutic use of a clinical stage CCR2 inhibitor, CCX872, in obesity-associated steatohepatitis

Abstract

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a common condition, in which hepatic steatosis is present in up to a third of individuals, whereas the more severe non-alcoholic steatohepatitis (NASH) is seen in about 10%. NAFLD is closely associated with the metabolic syndrome: up to 75% of people with diabetes mellitus, and almost all morbidly obese individuals, have NALFD. Obesity-associated macrophage infiltration of adipose and hepatic tissue is mediated by C-C chemokine receptor type 2 (CCR2), where CCR2+ CD11b+ F4/80+ macrophages contribute to chronic inflammation and insulin resistance. We investigated the efficacy of a small molecule inhibitor of CCR2, CCX872, which is in phase 1 clinical development, for treatment of obesity-associated hepatic steatohepatitis in mice. MethodsC57BL/6 mice aged 6 weeks were fed a high-fat diet for 16 weeks. After 8 weeks on this diet, mice were treated with CCX872 (ChemoCentryx, Mountain View, CA, USA) 30 mg/kg once daily or vehicle, both administered subcutaneously. Liver injury was assessed with serum alanine aminotransferase concentration, liver triglyceride content, and flow cytometry of infiltrating cells. Adipose tissue macrophage infiltration was assessed with flow cytometry. Insulin sensitivity was measured by glucose and insulin challenges. Groups were compared with two-tailed Student's t tests. FindingsMice treated with CCX872 had better insulin sensitivity (p<0·001) and glucose tolerance (p<0·001) than those treated with vehicle. Treatment with CCX872 significantly reduced alanine aminotransferase concentrations compared with vehicle-treated mice (mean 252·5 U/L [SD 185] vs 532·8 [353·6], p=0·028). Hepatic triglyceride accumulation was significantly lower in CCX872-treated mice (mean 159·9 mg/g [SD 2·6] vs 296·6 [98·5], p<0·01). Analysis of infiltrating cells by fluorescence-activated cell sorting showed reduced accumulation of CD11b+ F4/80+ macrophages in liver in CCX872-treated mice compared with vehicle-treated mice (mean 93% of CD45+ cells [SD 2·2] vs 16·0 [1·9], p=0·03; mean fluorescence intensity [MFI] 6919 [SD 107·7] vs 7365 [162·9], p=0·04) and in omental adipose tissue (9·2% of CD45+ cells [1·9] vs 21·8 [3·7], p=0·02; MFI 6212 [469·2] vs 7952 [379·5], p=0·02). InterpretationTreatment with a clinical-stage small molecule inhibitor of CCR2 improved steatohepatitis and insulin sensitivity in mice kept on a high-fat diet. FundingUK Medical Research Council.