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  • Emerging evidence has shown that pharmacological FXR agonism

    2022-06-15

    Emerging evidence has shown that pharmacological FXR agonism attenuates chronic alcohol treatment-induced liver injury and steatosis [18], [19], while whole-body FXR knockout worsens alcohol-induced liver injury [19]. This suggests that FXR plays an important role in ALD development. However, deficiency of FXR in the whole body leads to increased BA levels thereby making it difficult to determine the independent effects of FXR from that of BAs on ALD severity. In order to study the tissue specific roles of FXR in ALD development, hepatocyte-specific FXR knockout (FXRhep−/−) mice were used in this study to determine the contribution of hepatocyte FXR deficiency in the well-developed ALD mouse model, Lieber-DeCarli alcohol-containing diet plus one binge dose [20]. Importantly, the FXRhep−/− mice lack FXR in hepatocytes but show similar BA levels to that of wild type (WT) mice.
    Materials and methods
    Results
    Discussion FXR is a critical sensor for BA homeostasis in the body by regulating BA synthesis, transport and metabolism. In addition to regulating BA biosynthesis, FXR protects the liver from chemical-induced injury and inflammation, and promotes liver regeneration. Activation of FXR has recently been shown to protect against liver injury induced by CCl4 and acetaminophen [13], [14]. Activation of FXR may antagonize NF-κB signaling to decrease proinflammatory cytokine production in the liver and decrease LPS-induced hepatic inflammation [2], [3]. Studies have shown that FXR activation can protect the liver from alcohol-induced liver injury, while deletion of FXR in mice worsens the alcoholic liver disease [18], [19]. All these previously described studies were performed by systemic activation or deficiency of FXR leaving the tissue specific roles of FXR in ALD development unclear. Determining these tissue specific roles of FXR in ALD pathogenesis is of great importance as it is well known that the functions of FXR from different organs vary; for example intestinal FXR playing a major role in suppressing bile Cy5 RNA synthesis [7], [9], [21]. Moreover, systemic FXR alterations, either agonism or whole-body deficiency, are accompanied by changes in BA levels. BAs can cause cell injury, apoptosis, inflammation and tumorigenesis, and therefore alterations of BA levels in studies using systemic FXR models can confound the interpretation of study findings [15]. The FXRhep−/− mice present with a normal BA pool size [9], which makes them useful to study the direct effects of hepatic FXR deficiency on ALD development independent of the effects of increased BA pool size. The current study showed that deletion of the FXR gene only in hepatocytes did not deteriorate alcohol-induced hepatocyte ballooning, inflammation and injury. This was revealed by unchanged liver histopathology, activities of serum ALT and ALP, (Fig 1, Fig. 2), and expression of genes encoding pro-inflammatory factors (Fig. 3). However, hepatic FXR deficiency disturbed BA homeostasis, and slightly increased hepatic microsteatosis and collagen deposition (Fig. 2), indicating hepatic FXR might play some role in ALD progression. One of the mechanisms may be that the disturbance of BA homeostasis after alcohol treatment may have sensitized the liver to alcohol-induced injury. But more studies are needed to investigate this hypothesis. In our study, hepatocyte specific FXR deficiency had only minor effects on ALD development. This contrasts to other studies which describe how whole-body FXR deficiency in mice increases ALD severity and systemic activation of FXR Cy5 RNA attenuates ALD severity [18], [19]. The collective findings from our study and the previous reports therefore indicate that BAs or FXR deficiency in tissues other than the liver might be more important for ALD development. FXR signaling in the intestine is able to protect the integrity of the intestines; intestine integrity and defense against bacteria were reported to be compromised in FXR−/− mice [21], [22]. As alcohol has been demonstrated to induce hepatic oxidative stress and inflammation from gut bacterial-derived LPS [2], [4], [23], this indicates that intestinal FXR deficiency might be a more important mediator for alcohol-induced liver injury. Consistent with this hypothesis are the findings of a recent study which showed that the FXR/FGF15/FGFR4 axis protects the liver from ALD progression through maintaining BA homeostasis and modifying gut microflora [24]. However, additional studies are still needed to clarify the effects and mechanisms of intestinal FXR and BAs in maintaining intestinal integrity against gut leakage and inhibiting gut microbiota overgrowth and translocation.