ABSTRACT
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 (NCoR1Hep-/-) 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 NCoR1Hep-/- mice. We showed that after ALD was established, NCoR1Hep-/- 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 ß-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.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Fatty Liver , Liver Diseases, Alcoholic , Animals , Chemokines/metabolism , Disease Models, Animal , Epigenesis, Genetic , Ethanol/toxicity , Hepatocytes/metabolism , Inflammation/metabolism , Ligands , Liver/metabolism , Liver Diseases, Alcoholic/pathology , Macrophages/metabolism , Mice , Mice, Knockout , Nuclear Receptor Co-Repressor 1/genetics , Nuclear Receptor Co-Repressor 1/metabolismABSTRACT
To effectively utilize the vegetation on grain-for-green slopes in the wind-water erosion crisscross region, it is necessary to determine the reasonable vegetation utilization intensity. We set up runoff plots on slopes which were not cultivated and were closed for many years in the Liudaogou catchment, a typical catchment in wind-water erosion crisscross region of the Loess Plateau. With artificial simulated rainfall experiments, the characteristics of runoff and sediment yield on slopes (10°, 20° and 30°) under different utilization intensity of vegetation were studied to select the reasonable utilization intensity. The results showed that the runoff rate in the process of rainfall simulation could be divided into two periods: rapidly increasing in the initial period and slow increasing or quasi-steady state in the middle and late periods. The variation of erosion rate during the rainfall was dependent on the slope. The utilization intensity had a significant effect on the runoff yield, which increased with the increasing utilization intensities. The slope gradient had a significant effect on the sediment yield, with the variation of sediment yield with slope gradient being: 20°>30°>10°. Compared with the unused (natural) plots, the relative runoff and sediment increased with increasing utilization intensities. Predicted based on the rainfall data, annual soil erosion amount on the slope would be basically lower than the tolerance level of soil loss when the vegetation cover on the slope surface reached 25% in 15 years after abandoning reclamation. More attention should be paid to the restoration and management of vegetation on the slope of 20° in this area.
