Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption

Kim, Young-Chae; Byun, Sangwon; Seok, Sunmi; Guo, Grace L.; Xu, H. Eric; Kemper, Byron; Kemper, Jongsook Kim

doi:10.1053/j.gastro.2018.11.061

Cited by 45 publications

(46 citation statements)

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“…To examine the role of FGF15/19 in repression of lipogenic genes, the global expression of genes in livers of mice treated with FGF19 was examined by RNA-seq. We used FGF19 since FGF15 is less stable, postprandial metabolic functions of these two enterokines are similar in general, and FGF19 has been utilized in previous mouse studies 10,11,20,22,36,37 . In FGF19-treated mice, 791 genes were downregulated, 951 were upregulated ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…FGF19 mediates its postprandial functions in part via Small Heterodimer Partner (SHP/NR0B2). FGF19mediated phosphorylation of SHP increases nuclear localization and gene repression activity of SHP, leading to transcription repression of bile acid synthesis, one-carbon cycle, and autophagy in the late fed state [18][19][20][21][22] . However, whether the FGF15/19 and FGF15/19-activated SHP have a physiological role in epigenetic repression of hepatic lipogenesis has not been shown.…”

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confidence: 99%

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Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

et al. 2020

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“…The nuclear localization and gene regulatory function of SHP are increased by FGF15/19 signaling in the late fed state, which provides a physiological model to study regulation of miR‐210 by SHP. Notably, hepatic miR‐210 levels in WT mice were decreased after refeeding for 6 hours after overnight fasting, but these decreases were blunted in both SHP knockout (KO) and FGF15 KO mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

et al. 2020

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BaCKgRoUND aND aIMS:Bile acids (BAs) are important regulators of metabolism and energy balance, but excess BAs cause cholestatic liver injury. The histone methyltransferase mixed-lineage leukemia-4 (MLL4) is a transcriptional coactivator of the BA-sensing nuclear receptor farnesoid X receptor (FXR) and epigenetically up-regulates FXR targets important for the regulation of BA levels, small heterodimer partner (SHP), and bile salt export pump (BSEP). MLL4 expression is aberrantly down-regulated and BA homeostasis is disrupted in cholestatic mice, but the underlying mechanisms are unclear. appRoaCH aND ReSUltS: We examined whether elevated microRNA-210 (miR-210) in cholestatic liver promotes BA-induced pathology by inhibiting MLL4 expression. miR-210 was the most highly elevated miR in hepatic SHP-downregulated mice with elevated hepatic BA levels. MLL4 was identified as a direct target of miR-210, and overexpression of miR-210 inhibited MLL4 and, subsequently, BSEP and SHP expression, resulting in defective BA metabolism and hepatotoxicity with inflammation. miR-210 levels were elevated in cholestatic mouse models, and in vivo silencing of miR-210 ameliorated BA-induced liver pathology and decreased hydrophobic BA levels in an MLL4-dependent manner. In gene expression studies, SHP inhibited miR-210 expression by repressing a transcriptional activator, Kruppel-like factor-4 (KLF4). In patients with primary biliary cholangitis/ cirrhosis (PBC), hepatic levels of miR-210 and KLF4 were highly elevated, whereas nuclear levels of SHP and MLL4 were reduced. CoNClUSIoNS:Hepatic miR-210 is physiologically regulated by SHP but elevated in cholestatic mice and patients with PBC, promoting BA-induced liver injury in part by targeting MLL4. The miR-210-MLL4 axis is a potential target for the treatment of BA-associated hepatobiliary disease.

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“…This may reflect the organ specificity of the transcriptional regulation on SHP gene, and may reflect the different roles played by liver and SI in cholesterol metabolism. In SI, SHP phosphorylation by FGF15 (fibroblast growth factor 15) during post-prandial state is necessary for the inhibition of SREBF2 (sterol regulatory element binding transcription factor 2) activity, which leads to the repression of intestinal NPC1l1 expression and cholesterol absorption (97). In our study, the negative regulation of SHP on SREBF2 and cholesterol biosynthesis may also be reflected in the WGCNA network, where SHP belonged to SI(Yellow), a module negatively correlated with VA, while SREBF2 and HMGCR belonged to SI(Red), a module positively correlated with VA (Figure 15).…”

Section: Regulation Of Mmp9 (In Macrophage Dcs and Intestinal Epithementioning

confidence: 99%

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

Chai¹,

Lyu²,

Chen³

et al. 2019

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Vitamin A (VA) deficiency remains prevalent in resource limited countries, affecting over 250 million preschool aged children. Vitamin A deficiency is associated with reduced 2 intestinal barrier function and increased risk of mortality due to mucosal infection. Citrobacter rodentium (C. rodentium) infection in mice is a model for diarrheal diseases in humans. During C. rodentium infection, vitamin A deficient (VAD) mice displayed reduced survival rate and pathogen clearance compared to their vitamin A sufficient (VAS) counterparts. Objectives: To characterize and compare the impact of vitamin A (VA) deficiency on gene expression patterns in the small intestine (SI) and the colon, and to discover novel target genes in VA-related biological pathways. Methods: vitamin A deficient (VAD) mice were generated by feeding VAD diet to pregnant C57/BL6 dams and their post-weaning offspring. Total mRNA extracted from SI and colon were sequenced using Illumina HiSeq 2500 platform. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to characterize expression patterns and co-expression patterns. Results:The comparison between VAS and VAD groups detected 49 and 94 DEGs in SI and colon, respectively. According to GO information, DEGs in the SI demonstrated significant enrichment in categories relevant to retinoid metabolic process, molecule binding, and immune function. Immunity related pathways, such as "humoral immune response" and "complement activation," were positively associated with VA in SI. On the contrary, in colon, "cell division" was the only enriched category and was negatively associated with VA. Three co-expression modules showed significant correlation with VA status in SI and were identified as modules of interest. Those modules contained four known retinoic acid targets. Therefore we have prioritized the other module members (e.g. Mbl2, Mmp9, Cxcl14, and Nr0b2) to be investigated as candidate genes regulated by VA. Also in SI, markers of two cell types, Mast cell and Tuft cell, were found altered by VA status. Comparison of co-expression modules between SI and colon indicated distinct regulatory networks in these two organs. Material and MethodsAnimals. C57BL/6 mice, originally purchased from Jackson Laboratories (Bar Harbor, MN), were bred and maintained at the Pennsylvania State University (University Park, PA) for experiments. Mice were exposed to a 12 hour light, 12 hour dark cycle with ad libitum access to food and water. All animal experiments were performed according to the Pennsylvania State University's Institutional Animal Care and Use Committee (IACUC) guideline (IACUC # 43445). Vitamin A deficient (VAD) and vitamin A sufficient (VAS) mice were generated as previously described (23,(27)(28)(29). Briefly, VAS or VAD diets were fed to pregnant mothers and the weanlings. VAS diet contained 25 μg of retinyl acetate per day whereas VAD diet did not contain any VA. At weaning, mice were maintained on their respective d...

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Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption

Cited by 45 publications

References 46 publications

Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

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