%0 Journal Article %T Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration %A Yin Fan %A Wu Miao-miao %A Wei Xiao-li %A Ren Rui-xue %A Liu Meng-hua %A Chen Chong-qing %A Yang Liu %A Xie Rui-qian %A Jiang Shan-yue %A Wang Xue-fu %A Wang Hua %J Acta Pharmacologica Sinica %D 2022 %B 2022 %9 %! Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration %K %X Nuclear receptor corepressor 1 ( NCoR1 ) is a corepressor of the epigenetic regulation of gene transcription that has important functions in metabolism and inflammation, but little is known about its role in alcohol-associated liver disease (ALD). In this study, we developed mice with hepatocyte-specific NCoR1 knockout ( NCoR1 Hep−/− ) using the albumin-Cre/LoxP system and investigated the role of NCoR1 in the pathogenesis of ALD and the underlying mechanisms. The traditional alcohol feeding model and NIAAA model of ALD were both established in wild-type and NCoR1 Hep−/− mice. We showed that after ALD was established, NCoR1 Hep−/− mice had worse liver injury but less steatosis than wild-type mice. We demonstrated that hepatocyte-specific loss of NCoR1 attenuated liver steatosis by promoting fatty acid oxidation by upregulating BMAL1 (a circadian clock component that has been reported to promote peroxisome proliferator activated receptor alpha ( PPARα )-mediated fatty β-oxidation by upregulating de novo lipid synthesis). On the other hand, hepatocyte-specific loss of NCoR1 exacerbated alcohol-induced liver inflammation and oxidative stress by recruiting monocyte-derived macrophages via C-C motif chemokine ligand 2 (CCL2). In the mouse hepatocyte line AML12, NCoR1 knockdown significantly increased ethanol-induced CCL2 release. These results suggest that hepatocyte NCoR1 plays distinct roles in controlling liver inflammation and steatosis, which provides new insights into the development of treatments for steatohepatitis induced by chronic alcohol consumption. %U http://www.chinaphar.com/article/view/10666 %V 43 %N 9 %P 2351–2361 %@ 1745-7254