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

Abstract Background Non-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 t...

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Bibliographic Details
Published in:The Lancet (British edition) 2014-02, Vol.383, p.S78-S78
Main Authors: Parker, Richard, Dr, Walters, Matthew, PhD, Ertl, Linda, Ebsworth, Karen, Tan, Joanne, PhD, McMahon, Jeff, PhD, Powers, Jay, PhD, Adams, David, Prof, Jaen, Juan, PhD, Schall, Tom, PhD
Format: Article
Language:English
Subjects:
Adipose tissue
Diet
Fluorescence
Infiltration
Internal Medicine
Liver
Medical research
Metabolic disorders
Obesity
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Summary:Abstract Background Non-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. Methods C57BL/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. Findings Mice treated with CCX872 had better insulin sensitivity (p
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(14)60341-X