Bile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed-state metabolism. Since the detergent-like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. BA homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary bile acid receptor, farnesoid X receptor (FXR), and small heterodimer partner (SHP) that inhibits BA synthesis by recruiting repressive histone-modifying enzymes. Although histone modifiers have been shown to regulate BA-responsive genes, their in vivo functions remain unclear. Here we show that lysine-specific histone demethylase1 (LSD1) is directly induced by BA-activated FXR, is recruited to BA synthetic genes, Cyp7a1 and Cyp8b1, and the BA uptake transporter gene, Ntcp, and removes a gene-activation mark, tri-methylated histone H3 lysine-4, leading to gene repression. LSD1 recruitment was dependent on SHP, and LSD1-mediated demethylation of H3K4-me3 was required for additional repressive histone modifications, H3K9/K14 deacetylation and H3K9 methylation. BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenoviral-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum AST/ALT levels, and hepatic inflammation. This study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the FXR and SHP that reduces hepatic BA levels and protects the liver against BA toxicity.

Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. Fibroblast Growth Factor-15/19 (mouse FGF15, human FGF19) are bile acid-induced late fed-state gut hormones that decrease hepatic lipid levels by unclear mechanisms. We show that FGF15/19 and FGF15/19-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF19, have overlapping CpG islands. FGF19 treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to epigenetic repression via DNA methylation. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. In conclusion, FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.

Background & Aims: The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in intestines of mice, including their regulation of expression of the cholesterol transporter NPC1-like intracellular cholesterol transporter 1 (NPC1L1) and cholesterol absorption. Methods: We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-seq analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 was examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP-knockout mice and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells.

In 2014, the South Korean government initiated the “Nutria Eradication Project” to actively manage and control populations of nutria, an invasive alien species that threatens national biodiversity. In the present study, we examined domestic nutria habitats in 2014 to 2018 and analyzed spatial shifts in habitat distribution to develop management policies and eradication strategies for the South Korean Ministry of Environment. A total of 27,487 nutria individuals were captured over five years upon the initiation of the eradication project. We found that the number of habitat tracks decreased from 1510 in 19 administrative districts in 2014 to 176 in 14 districts in 2018. We examined the distribution of nutria habitat tracks and found a northwestward shift at an average angle of 313.9° and 46,656.9 m. This distribution shift prompted improvements in control policies focused on nutria capture to suppress rodent movement and shifting distributions. We redefined the spatial scope of our control regions accordingly and established isolated environments in each region to prevent further spread. Additionally, resource management was focused in areas showing habitat expansion. Overall, we observed an estimated 54% decrease in nutria habitat tracks from 2016 to 2017. Our results have since been enacted in government policies and provide a basis for establishing flexible strategies for effectively controlling nutria habitats and populations. In 2017, the South Korean government allocated additional funds for research and for the development of further control strategies working toward the project’s goals.

Aberrantly elevated expression in obesity of microRNAs (miRNAs), including the miRNA miR-802, contributes to obesity-associated metabolic complications, but the mechanisms underlying the elevated expression are unclear. Farnesoid X receptor (FXR), a key regulator of hepatic energy metabolism, has potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced small heterodimer partner (SHP) regulates expression of miR-802 to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of miR-802 by aromatic hydrocarbon receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In patients with nonalcoholic fatty liver disease (NAFLD) and in obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the miR-802 promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR-802 levels, insulin resistance, and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.

Thymosin β10 (Tβ10) regulates actin dynamics as a cytoplasm G-actin sequestering protein. Previously, we have shown that Tβ10 diminishes tumor growth, angiogenesis, and proliferation by disrupting actin and by inhibiting Ras. However, little is known about its mechanism of action and biological function. In the present study, we establish a new gene therapy model using a genetically modified adenovirus, referred to as Ad.TERT.Tβ10, that can overexpress the Tβ10 gene in cancer cells. This was accomplished by replacing the native Tβ10 gene promoter with the human TERT promoter in Ad.TERT.Tβ10. We investigated the cancer suppression activity of Tβ10 and found that Ad.TERT.Tβ10 strikingly induced cancer-specific expression of Tβ10 as well as apoptosis in a co-culture model of human primary ovarian cancer cells and normal fibroblasts. Additionally, Ad.TERT.Tβ10 decreased mitochondrial membrane potential and increased reactive oxygen species (ROS) production. These effects were amplified by co-treatment with anticancer drugs, such as paclitaxel and cisplatin. These findings indicate that the rise in ROS production due to actin disruption by Tβ10 overexpression increases apoptosis of human ovarian cancer cells. Indeed, the cancer-specific overexpression of Tβ10 by Ad.TERT.Tβ10 could be a valuable anti-cancer therapeutic for the treatment of ovarian cancer without toxicity to normal cells.

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Aberrantly elevated expression in obesity of microRNAs (miRs), including miR-802, contributes to obesity-associated metabolic complications but the mechanisms underlying the elevated expression are unclear. Farnesoid-X-Receptor (FXR), a key regulator of hepatic energy metabolism, has great potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced Small Heterodimer Partner (SHP) regulates expression of <i>miR-802</i> to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of <i>miR-802 </i>by<i> </i>Aromatic Hydrocarbon Receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In non-alcoholic fatty liver disease patients and obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the <i>miR-802</i> promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of <i>miR-802</i> by FXR-SHP is defective in obesity, resulting in increased <i>miR-802</i> levels, insulin resistance and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.