The translocation of bacteria and bacterial products into the circulation contributes to alcoholic liver disease. Intestinal bacterial overgrowth is common in patients with alcoholic liver disease. The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in alcoholic liver disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation occurred prior to changes observed in the microbiome. Quantitative changes in the intestinal microflora of these animals were assessed first using conventional culture techniques in the small and large intestine. Although we found no difference after 1 day or 1 week, intestinal bacterial overgrowth was observed in the gastrointestinal tract of mice fed alcohol for 3 weeks compared with control mice fed an isocaloric liquid diet. Because <20% of all gastrointestinal bacteria can be cultured using conventional methodologies, we performed massively parallel pyrosequencing to further assess the qualitative changes in the intestinal microbiome following alcohol exposure. Sequencing of 16S ribosomal RNA genes revealed a relative abundance of Bacteroidetes and Verrucomicrobia bacteria in mice fed alcohol compared with a relative predominance of Firmicutes bacteria in control mice. With respect to the host's transcriptome, alcohol feeding was associated with down-regulation in gene and protein expression of bactericidal c-type lectins Reg3b and Reg3g in the small intestine. Treatment with prebiotics partially restored Reg3g protein levels, reduced bacterial overgrowth, and lessened alcoholic steatohepatitis. Conclusion: Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis. Intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to alcoholic steatohepatitis. (Hepatology 2011)

Chronic alcohol consumption is associated with steatohepatitis and cirrhosis, enhancing the risk for hepatocellular carcinoma. RNA polymerase (pol) III transcribes a variety of small, untranslated RNAs, including tRNAs and 5S rRNAs, which determine the biosynthetic capacity of cells. Increased RNA pol III-dependent transcription, observed in transformed cells and human tumors, is required for oncogenic transformation. Given that alcohol consumption increases risk for liver cancer, we examined whether alcohol regulates this class of genes. Ethanol induces RNA pol III-dependent transcription in both HepG2 cells and primary mouse hepatocytes in a manner that requires ethanol metabolism and the activation of JNK1. This regulatory event is mediated, at least in part, through the ability of ethanol to induce expression of the TFIIIB components, Brf1, and the TATA-binding protein (TBP). Induction of TBP, Brf1, and RNA pol III-dependent gene expression is driven by enhanced c-Jun expression. Ethanol promotes a marked increase in the direct recruitment of c-Jun to TBP, Brf1, and tRNA gene promoters. Chronic alcohol administration in mice leads to enhanced expression of TBP, Brf1, tRNA, and 5S rRNA gene transcription in the liver. These alcohol-dependent increases are more pronounced in transgenic animals that express the HCV NS5A protein that display increased incidence of liver tumors. Together, these results identify a new class of genes that are regulated by alcohol through the co-regulation of TFIIIB components and define a central role for c-Jun in this process.

Fibroblast growth factor (FGF) signaling and ␤-catenin activation have been shown to be crucial for early embryonic liver development. This study determined the significance of FGF10-mediated signaling in a murine embryonic liver progenitor cell population as well as its relation to ␤-catenin activation. We observed that

Background & Aims Liver X receptors (LXRs) are lipid-activated nuclear receptors with important roles in cholesterol transport, lipogenesis, and anti-inflammatory signaling. Hepatic stellate cells (HSCs) activate during chronic liver injury and mediate the fibrotic response. These cells are also major repositories for lipids, but the role of lipid metabolism during stellate cell activation remains unclear. Here we show that LXR signaling is an important determinant of stellate cell activation and susceptibility to fibrotic liver disease. Methods Immortalized and primary stellate cells purified from mice were treated with highly specific LXR ligands. Carbon tetrachloride (CCl4) and methionine choline deficiency (MCD) were used as chronic liver injury models. Reciprocal bone marrow transplants were performed to test the importance of hematopoietically-derived cells to the fibrotic response. Results LXR ligands suppressed markers of fibrosis and stellate cell activation in primary mouse stellate cells. Lxrαβ −/− stellate cells produce increased levels of inflammatory mediators and conditioned media from Lxrαβ−/− cells increases the fibrogenic program of wild-type cells. Furthermore, Lxrαβ−/− stellate cells exhibit altered lipid morphology and increased expression of fibrogenic genes, suggesting they are primed for activation. In vivo, Lxrαβ−/− mice have marked susceptibility to fibrosis in two injury models. Bone marrow transplants point to altered stellate cell function, rather than hematopoietic cell inflammation, as the primary basis for the Lxrαβ−/− phenotype. Conclusions These results reveal an unexpected role for LXR signaling and lipid metabolism in the modulation of hepatic stellate cell function.