Activation of Bile Acid Biosynthesis by the p38 Mitogen-activated Protein Kinase (MAPK)

Xu, Zhumei; Tavares-Sanchez, Olga Lidia; Li, Quanzhong; Fernando, Josephine; Rodriguez, Carmen; Studer, Elaine; Pandak, William M.; Hylemon, Phillip B.; Gil, Gregorio

doi:10.1074/jbc.m611481200

Cited by 40 publications

(13 citation statements)

References 34 publications

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“…Both phosphorylation and lysine acetylation of HNF4A affect its transcriptional activity ( 31 – 33 ). Therefore, we first examined changes in post-translational modifications of HNF4A after ROCK inhibition, but detected no changes in such modifications under our experimental conditions (Supplementary Figure S6A).…”

Section: Resultsmentioning

confidence: 99%

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression

Yoshikawa

Otsuka

et al. 2015

Nucleic Acids Res

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The reduced expression levels and functional impairment of global miRNAs are related to various human diseases, including cancers. However, relatively little is known about how global miRNA function may be upregulated. Here, we report that global miRNA function can be enhanced by Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors. The regulation of miRNA function by ROCK inhibitors is mediated, at least in part, by poly(A)-binding protein-interacting protein 2 (PAIP2), which enhances poly(A)-shortening of miRNA-targeted mRNAs and leads to global upregulation of miRNA function. In the presence of a ROCK inhibitor, PAIP2 expression is enhanced by the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) through increased ROCK1 nuclear localization and enhanced ROCK1 association with HNF4A. Our data reveal an unexpected role of ROCK1 as a cofactor of HNF4A in enhancing PAIP2 transcription. ROCK inhibitors may be useful for the various pathologies associated with the impairment of global miRNA function.

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Section: Resultsmentioning

confidence: 99%

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression

Yoshikawa

Otsuka

et al. 2015

Nucleic Acids Res

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“…The phosphorylation of HNF4α regulates specific genes by affecting DNA binding and/or cofactor recruitment (15–18). The HNF4α isoforms are generated by alternative promoters together with alternative splicing of the corresponding exons (19–21).…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of Native Hepatocyte Nuclear Factor-4α (HNF4α) Isoforms, Phosphorylation Status, and Interactive Cofactors

Daigo

Kawamura

Ohta

et al. 2011

Journal of Biological Chemistry

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Hepatocyte nuclear factor-4α (HNF4α, NR2A1) is a nuclear receptor that has a critical role in hepatocyte differentiation and the maintenance of homeostasis in the adult liver. However, a detailed understanding of native HNF4α in the steady-state remains to be elucidated. Here we report the native HNF4α isoform, phosphorylation status, and complexes in the steady-state, as shown by shotgun proteomics in HepG2 hepatocarcinoma cells. Shotgun proteomic analysis revealed the complexity of native HNF4α, including multiple phosphorylation sites and inter-isoform heterodimerization. The associating complexes identified by label-free semiquantitative proteomic analysis include the following: the DNA-dependent protein kinase catalytic subunit, histone acetyltransferase complexes, mRNA splicing complex, other nuclear receptor coactivator complexes, the chromatin remodeling complex, and the nucleosome remodeling and histone deacetylation complex. Among the associating proteins, GRB10 interacting GYF protein 2 (GIGYF2, PERQ2) is a new candidate cofactor in metabolic regulation. Moreover, an unexpected heterodimerization of HNF4α and hepatocyte nuclear factor-4γ was found. A biochemical and genomewide analysis of transcriptional regulation showed that this heterodimerization activates gene transcription. The genes thus transcribed include the cell death-inducing DEF45-like effector b (CIDEB) gene, which is an important regulator of lipid metabolism in the liver. This suggests that the analysis of the distinctive stoichiometric balance of native HNF4α and its cofactor complexes described here are important for an accurate understanding of transcriptional regulation.

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“…In addition to its long recognized function as a detergent, bile acids are now known as important signaling molecules for cells in the liver and gastrointestinal tract [4,15,16] and are involved in the regulation of lipid and glucose metabolism [4–6]. Bile acids can activate several nuclear receptors (FXR-α, PXR, vitamin D receptor (NR12)) and G-protein-coupled receptor (GPCR) membrane-type bile acid receptor (TGR5/M-BAR) [4,5,17].…”

Section: Discussionmentioning

confidence: 99%

Murine model of long-term obstructive jaundice

Aoki

Yang

et al. 2016

Journal of Surgical Research

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Background With the recent emergence of conjugated bile acids as signaling molecules in cancer, a murine model of obstructive jaundice by cholestasis with long-term survival is in need. Here, we investigated the characteristics of 3 murine models of obstructive jaundice. Methods C57BL/6J mice were used for total ligation of the common bile duct (tCL), partial common bile duct ligation (pCL), and ligation of left and median hepatic bile duct with gallbladder removal (LMHL) models. Survival was assessed by Kaplan-Meier method. Fibrotic change was determined by Masson-Trichrome staining and Collagen expression. Results 70% (7/10) of tCL mice died by Day 7, whereas majority 67% (10/15) of pCL mice survived with loss of jaundice. 19% (3/16) of LMHL mice died; however, jaundice continued beyond Day 14, with survival of more than a month. Compensatory enlargement of the right lobe was observed in both pCL and LMHL models. The pCL model demonstrated acute inflammation due to obstructive jaundice 3 days after ligation but jaundice rapidly decreased by Day 7. The LHML group developed portal hypertension as well as severe fibrosis by Day 14 in addition to prolonged jaundice. Conclusion The standard tCL model is too unstable with high mortality for long-term studies. pCL may be an appropriate model for acute inflammation with obstructive jaundice but long term survivors are no longer jaundiced. The LHML model was identified to be the most feasible model to study the effect of long-term obstructive jaundice.

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Activation of Bile Acid Biosynthesis by the p38 Mitogen-activated Protein Kinase (MAPK)

Cited by 40 publications

References 34 publications

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression

Proteomic Analysis of Native Hepatocyte Nuclear Factor-4α (HNF4α) Isoforms, Phosphorylation Status, and Interactive Cofactors

Murine model of long-term obstructive jaundice

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