The liver and intestine play crucial roles in maintaining bile acid homeostasis. Here, we demonstrate that fibroblast growth factor 15 (FGF15) signals from intestine to liver to repress the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the first and rate-limiting step in the classical bile acid synthetic pathway. FGF15 expression is stimulated in the small intestine by the nuclear bile acid receptor FXR and represses Cyp7a1 in liver through a mechanism that involves FGF receptor 4 (FGFR4) and the orphan nuclear receptor SHP. Mice lacking FGF15 have increased hepatic CYP7A1 mRNA and protein levels and corresponding increases in CYP7A1 enzyme activity and fecal bile acid excretion. These studies define FGF15 and FGFR4 as components of a gut-liver signaling pathway that synergizes with SHP to regulate bile acid synthesis.

Obstruction of bile flow results in bacterial proliferation and mucosal injury in the small intestine that can lead to the translocation of bacteria across the epithelial barrier and systemic infection. These adverse effects of biliary obstruction can be inhibited by administration of bile acids. Here we show that the farnesoid X receptor (FXR), a nuclear receptor for bile acids, induces genes involved in enteroprotection and inhibits bacterial overgrowth and mucosal injury in ileum caused by bile duct ligation. Mice lacking FXR have increased ileal levels of bacteria and a compromised epithelial barrier. These findings reveal a central role for FXR in protecting the distal small intestine from bacterial invasion and suggest that FXR agonists may prevent epithelial deterioration and bacterial translocation in patients with impaired bile flow.bacteria ͉ biliary obstruction ͉ epithelial barrier ͉ ileum

Lipid droplets (LDs) are emerging cellular organelles that are of crucial importance in cell biology and human diseases. In this study, we present our screen of ∼4,700 Saccharomyces cerevisiae mutants for abnormalities in the number and morphology of LDs; we identify 17 fld (few LDs) and 116 mld (many LDs) mutants. One of the fld mutants (fld1) is caused by the deletion of YLR404W, a previously uncharacterized open reading frame. Cells lacking FLD1 contain strikingly enlarged (supersized) LDs, and LDs from fld1Δ cells demonstrate significantly enhanced fusion activities both in vivo and in vitro. Interestingly, the expression of human seipin, whose mutant forms are associated with Berardinelli-Seip congenital lipodystrophy and motoneuron disorders, rescues LD-associated defects in fld1Δ cells. Lipid profiling reveals alterations in acyl chain compositions of major phospholipids in fld1Δ cells. These results suggest that an evolutionally conserved function of seipin in phospholipid metabolism and LD formation may be functionally important in human adipogenesis.

Pluripotence in embryonic stem (ES) cells and the early mouse embryo is controlled by several key transcription factors such as Oct4, Sox2, Foxd3, Nanog, and signaling molecules such as STAT3, FGF4, FGF4 receptor, and LIF (4,11,18,22,32,35,51). The regulation of expression of these key factors is thus crucial for the maintenance of pluripotence and embryonic development. However, little is known about the upstream factors that regulate the expression of these genes. Oct4, a member of the POU homeodomain family of transcription factors, is the best studied of these factors. Recent studies have shown that Oct4 plays a critical role in embryonic development and cellular differentiation (38,43). Oct4 is expressed in totipotent and pluripotent stem cells of the pregastrulation embryo, primordial germ cells, and oocytes (37,44,47). Oct4 is also highly expressed in ES and embryonic carcinoma cell lines, such as P19 and F9 cells, and is rapidly down-regulated by differentiation induced with retinoic acid (RA) (6, 31). In ES cells, a less than twofold increase in the level of Oct4 mRNA causes the cells to differentiate into primitive endoderm and mesoderm, whereas reduction to less than 50% of normal levels triggers differentiation into trophectoderm (36). Moreover, targeted disruption of the Oct4 gene in mice results in embryonic death at the blastocyst stage and compacted morula cells that do not differentiate along the pluripotent inner cell mass lineage but instead differentiate into trophectodem (32).