1865-P: Dual Chemokine Receptor CCR2/CCR5 Antagonist Cenicriviroc Ameliorates Lipotoxicity-Induced Insulin Resistance and NASH in Mice

Abstract

Hepatic lipid accumulation drives innate immunity with recruitment of bone marrow-derived macrophages and activation of liver-resident Kupffer cells, leading to insulin resistance and nonalcoholic steatohepatitis (NASH) development. However, treatment options that target macrophage/Kupffer cells recruitment or activation to halt the insulin resistance and NASH remain limited. A C-C chemokine receptor 2 (CCR2) plays a central role in macrophage recruitment. In addition, we reported that a different C-C chemokine receptor, CCR5, promotes insulin resistance and hepatic steatosis by regulating macrophage M1/M2 status. Here, we investigated the effect of cenicriviroc (CVC), a dual CCR2 and CCR5 receptor antagonist in a lipotoxic model of NASH with hepatic fibrosis and insulin resistance. Eight-week-old C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.015% CVC (CL+CVC) for 12 weeks. The liver histology, insulin sensitivity, and fibrogenesis were examined. The CVC administration decreased the increase in plasma ALT levels as well as liver triglyceride, cholesterol, and TBARS levels caused by the CL diet. In addition, CVC improved glucose intolerance and hyperinsulinemia in the CL group and augmented the insulin signal, assessed by IRβ and Akt phosphorylation in the liver. Flow cytometry analysis revealed that mice fed CL+CVC had 72% fewer CD11c+CD206- M1-like macrophages, but 94% more CD11c-CD206+M2-like macrophages than CL group, indicating that CVC caused an M2-dominant shift in macrophages/Kupffer cells in the liver. Furthermore, CVC attenuated hepatic fibrosis by repressing the activation of hepatic stellate cells (HSCs) and decreasing hydroxyproline content. Thus, CVC ameliorated lipotoxicity-induced insulin resistance and NASH with hepatic fibrosis by polarizing M2 macrophage and attenuating HSC activation. Disclosure T. Ota: None. G. Chen: None. M. Nagashimada: None. Funding Japan Ministry of Education, Culture, Sports, Science and Technology