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    • Ro 31-8220 Mesylate In the intestine ethanol exposure can ch

    2022-01-27

    In the intestine, ethanol exposure can change the composition of gut microbiota and promotes the growth of intestinal gram-negative bacteria, which results in the accumulation of endotoxins such as, LPS. Ethanol also impacts the integrity of the gastrointestinal mucosal barrier, increasing intestinal permeability of a variety of substances, including endotoxin, to the liver through portal circulation, therefore activating the innate immune response [1], [4]. Intestinal FXR is critical in the preservation of integrity and function of the intestinal mucosal barrier to prevent bacterial translocation [27], [28], and a recent study has demonstrated that intestinal FXR, FGF15 and microbiota contribute to ALD [26]. The most significant finding here was an increased hepatic Ro 31-8220 Mesylate of Cd14, the LPS receptor, supporting increased LPS signaling and potential disruption of the intestinal barrier. In summary, ethanol intake disturbs lipid metabolism and BA homeostasis, and FXR deficiency exacerbates ethanol-induced liver injury. The mechanism by which FXR protects the liver against ALD has yet to be determined. This study demonstrates FXR may regulate liver steatosis and inflammation through the modulation of BA homeostasis. These findings, in combination with those from our previous study, indicate a potential mechanism by which intestinal FXR helps to maintain intestinal epithelial integrity against gut-derived endotoxin and bacterial dislocation and protects against ethanol-induced liver injury [30]. Therefore, further studies using intestine-specific FXR deficient mice may shed further mechanistic insight into how FXR regulates the development of ALD. As FXR agonists are currently in clinical development, the findings from intestine-specific FXR knockout mice may provide scientific basis for a set of preventive strategies and provide therapeutic approaches for the treatment of ALD.
    Conflict of interest
    Acknowledgments
    Introduction Liver cirrhosis has been associated with alterations in renal functions. One of the major regulators in the development of liver cirrhosis and the associated renal impairment is nitric oxide (NO). NO is produced from endothelial NO synthase (eNOS) enzyme and had been found to be deficient in chronic renal failure patients (Passauer et al., 2005). Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA were detected in cirrhotic patients. It has been found that there is a close correlation between ADMA plasma levels and the degree of hepatic dysfunction (Trauner et al., 2011). Oxidative stress and inflammation are found to be responsible for increased synthesis and/or inhibition of catabolism of ADMA (Kwaśny-Krochin et al., 2012; Cichoż-Lach and Michalak, 2014). Additionally, Carello et al., 2006 found that ADMA elicits contractile effects on human renal arteries and increased plasma levels of ADMA had been associated with a decrease in renal plasma flow, increase in renovascular resistance, renal oxidative stress, endothelial dysfunction, and induction of glomerular and vascular fibrosis through a mechanism involving collagen and transforming growth factor β1 (TGFβ1) synthesis (Mihout et al., 2011). Regarding the metabolism of ADMA, it is performed by dimethylarginine dimethylaminohydrolases (DDAHs) which are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver (Mookerjee et al., 2015) and kidneys (Onozato et al., 2008). DDAH-1 was defined as a Farnesoid X receptor (FXR) target gene, synthetic FXR agonist increased hepatic DDAH-1 gene expression (Hu et al., 2012). The FXR is part of a family of nuclear hormone receptors that modulates the transcription of many inflammatory and cell-cycle control genes and is particularly abundant in the kidney and liver (Ali et al., 2015). Because FXR is the receptor of bile acids and is highly abundant in the kidney, it was anticipated that FXR may share in the regulation of renal water and sodium homeostasis and is involved in the development of fluid retention in liver cirrhosis. Both FXR endogenous agonist (bile acid) and synthetic ligand (GW4064) induce FXR mRNA expression in the kidney and in cultured renal collecting duct cells (Zhang et al., 2014).