RESUMO
Genetic and pharmacological activation of the transcription factor nuclear factor, erythroid derived 2, like 2 (Nrf2) alleviates high-fat diet (HFD)-induced obesity in mice; however, synthetic Nrf2 activators are not clinically available due to safety concerns. Dietary glucoraphanin (GR), a naturally occurring compound found in cruciferous vegetables that activates Nrf2 and induces its target antioxidant genes. We previously demonstrated that GR increased thermogenesis and mitigated HFD-induced obesity in lean healthy mice. In this study, we investigated the therapeutic effects of GR on pre-existing obesity and associated metabolic disorders, such as hepatic steatosis, with or without low-fat dietary intervention. Eight-week-old male C57BL/6J mice were fed an HFD for 9 weeks to induce obesity. Subsequently, these obese mice were fed either the HFD or a normal chow diet, supplemented with or without GR, for an additional 11 weeks. GR supplementation did not decrease the body weight of HFD-fed mice; however, it significantly reduced plasma alanine aminotransferase and aspartate aminotransferase levels and hepatic triglyceride accumulation. These improvements in liver damage by GR were associated with decreased expression levels of fatty acid synthesis genes and proinflammatory chemokine genes, suppressed c-Jun N-terminal kinase activation, and reduced proinflammatory phenotypes of macrophages in the liver. Moreover, metabolome analysis identified increased hepatic levels of adenosine 5'-monophosphate (AMP) in HFD-GR mice compared with those in HFD mice, which agreed with increased phosphorylation levels of AMP-activated protein kinase. Our results show that GR may have a therapeutic potential for treating obesity-associated hepatic steatosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00658-6.
RESUMO
The inhibition of hepatic macrophage and Kupfer cell recruitment and activation is a potential strategy for treating insulin resistance and nonalcoholic steatohepatitis (NASH). Cenicriviroc (CVC), a dual C-C chemokine receptor 2 (CCR2) and CCR5 antagonist, has shown antifibrotic activity in murine models of NASH and has been evaluated in clinical trials on patients with NASH. This study investigated the effects of CVC on macrophage infiltration and polarization in a lipotoxic model of NASH. 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. Macrophage recruitment and activation were assayed by immunohistochemistry and flow cytometry. CVC supplementation attenuated excessive hepatic lipid accumulation and peroxidation and alleviated glucose intolerance and hyperinsulinemia in the mice that were fed the CL diet. Flow cytometry analysis revealed that compared with the CL group, mice fed the CL + CVC diet had fewer M1-like macrophages, more M2-like macrophages, and fewer T cell counts, indicating that CVC caused an M2-dominant shift of macrophages in the liver. Similarly, CVC decreased lipopolysaccharide-stimulated M1-like macrophage activation, whereas it increased interleukin-4-induced M2-type macrophage polarization in vitro. In addition, CVC attenuated hepatic fibrosis by repressing hepatic stellate cell activation. Lastly, CVC reversed insulin resistance as well as steatosis, inflammation, and fibrosis of the liver in mice with pre-existing NASH. In conclusion, CVC prevented and reversed hepatic steatosis, insulin resistance, inflammation, and fibrogenesis in the liver of NASH mice via M2 macrophage polarization.