Abstract
Hepatic macrophages play a critical role in inflammation caused by alcohol feeding. During this process, variation of macrophage phenotypes triggers inflammatory responses in a variety of ways. Moreover, there is increasing evidence that Brain and Muscle Arnt-Like Protein-1 (Bmal1) is regarded as a key regulator of macrophage transformation. In our study, Bmal1 was detected to be low expressed in EtOH-fed mice tissue samples and ethanol-induced RAW264.7 cells. After hepatic specific overexpression of Bmal1, M1 macrophage markers were evidently down-regulated, while M2 markers were on the contrary, showing an upward trend. Furthermore, alcoholic liver lesions were also improved in alcohol feeding mice with overexpressed Bmal1. On this basis, we also found that the glycolytic pathway can regulate macrophage polarization. In vitro, blocking of glycolytic pathway can significantly inhibit M1-type polarization. Importantly, glycolysis levels were also restrained after Bmal1 overexpression. What’s more, Bmal1 exerts a negative regulatory effect on glycolysis by interacting with S100A9 protein. Further studies showed that the alleviation of alcoholic liver disease (ALD) by Bmal1 was associated with glycolytic pathway suppression and M1 macrophage polarization. In summary, we demonstrated that Bmal1 is a gene capable of relieving ALD, and this effect may provide new insights for altering macrophage phenotypes to regulate inflammatory responses in ALD.
Highlights
At present, liver disease has developed into the leading cause of diseases and death worldwide
The analysis showed that compared with the control diet (CD)-fed mice, the degree of liver injury was worse in the EtOH-fed mice
To get better acquainted with the mechanism by which Brain and Muscle Arnt-Like Protein-1 (Bmal1) regulated macrophage polarization, we looked for a signaling pathway which was involved in the process of macrophage polarization caused by Bmal1
Summary
Liver disease has developed into the leading cause of diseases and death worldwide. Long-term excessive drinking leads to structural abnormalities and dysfunction of hepatocyte, which further progresses to ALD. The initial manifestation of the disease is alcoholic fatty liver disease (AFL) with hepatocyte steatosis, necrosis, regeneration and so on a series of changes (Liu, 2014). It is well-known that inflammation, oxidative stress, drinking patterns, viral infection and cell damage are typical drivers of alcoholic liver injury. With Kupffer cells producing large amounts of the proinflammatory cytokine TNF-α, IL-1β, leading to the aggravation of ALD (Tsukamoto and Lu, 2001; Miller et al, 2011; Tilg et al, 2011; Lívero and Acco, 2016).
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