Friday, April 26, 2024
4/26/2024
Patients with alcoholic liver disease (ALD) often exhibit manifestations of cholestasis, a liver pathology defined by accumulation of hepatic bile acids (BAs), which are toxic and an important causative factor in hepatocyte death and liver injury in ALD. Excess hepatic BA concentration is a result of increased BA de novo synthesis and decreased BA secretion to bile. BA metabolism is regulated by farnesoid X receptor (FXR) signaling in intestine and liver. Previous study suggests that intestinal FXR is likely a major player to regulate hepatic BA synthesis. Intestinal FXR activation is regulated by gut lumen BA species and concentration. Primary BA chenodeoxycholic acid (CDCA) is an agonist of FXR, which is antagonized by taurine-ß-murine cholic acid (TßMCA). Previous studies have demonstrated that gut BA is dysregulated in ALD patients and in experimental ALD mice. Modulation of dysregulated BA signaling in the intestine improves experimental ALD. Interestingly, our preliminary data showed that, in the NIAAA binge-on-chronic alcohol feeding model, intestinal FXR mRNA was markedly reduced, along with decreased intestinal fibroblast growth factor (FGF) 15/19 (mouse/humans) and increased hepatic Cyp7a1 expression, elevated BA concentration and liver injury. Targeting intestinal FXR, both in transcription and in activation, may be a plausible strategy for inhibiting ALD. FXR transcription is regulated by microRNA194 (miR194), which is highly expressed in the intestine. Our preliminary data showed that alcohol feeding significantly increased intestinal miR194. Interestingly, miR194 is suppressed by taurine upregulated gene 1(TUG1), a long non-coding RNA regulated by taurine concentration. Therefore, it is likely that alcohol-induced miR194 causes a reduction of intestinal FXR in ALD. Supplementation of probiotic Lactobacillus rhamnosus GG (LGG) is protective against experimental ALD through multiple mechanisms. Our preliminary study showed that LGG suppressed alcohol-increased miR194 and -decreased FXR in the intestine. These previous and preliminary studies strongly suggest that LGG may exert its function in hepatic BA synthesis through modulation of intestinal miR194-FXR signaling. We thus hypothesize that alcohol exposure increases intestinal miR194 and suppresses FXR and FGF15 leading an increase in hepatic de novo BA synthesis and liver injury; and LGG supplementation inhibits intestinal miR194 and suppresses hepatic BA synthesis and liver injury in mice. To test our hypothesis, we design following specific aims: Aim 1 will determine the role of miR194 in the regulation of intestinal FXR signaling and hepatic BA homeostasis in ALD. Aim 2 will determine the role of intestinal miR194-FXR-FGF15 signaling in the protective effects of LGG on ALD. Aim 3 will identify the mechanism(s) of miR194 regulation in ALD. Collectively, the training and research proposed here will not only fill a significant need for the development of ALD treatments, but will also foster my development from a young scientist to a successful, independent investigator in the field of alcohol-induced organ disease.
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