Hepatocyte nuclear factor 4?? is implicated in endoplasmic reticulum stress???induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H Potential conflict of interest: Nothing to report.

Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Hepatology (Impact Factor: 11.06). 10/2008; 48(4):1242-50. DOI: 10.1002/hep.22439
Source: PubMed


Loss of the nuclear hormone receptor hepatocyte nuclear factor 4alpha (HNF4alpha) in hepatocytes results in a complex pleiotropic phenotype that includes a block in hepatocyte differentiation and a severe disruption to liver function. Recent analyses have shown that hepatic gene expression is severely affected by the absence of HNF4alpha, with expression of 567 genes reduced by > or =2.5-fold (P < or = 0.05) in Hnf4alpha(-/-) fetal livers. Although many of these genes are direct targets, HNF4alpha has also been shown to regulate expression of other liver transcription factors, and this raises the possibility that the dependence on HNF4alpha for normal expression of some genes may be indirect. We postulated that the identification of transcription factors whose expression is regulated by HNF4alpha might reveal roles for HNF4alpha in controlling hepatic functions that were not previously appreciated. Here we identify cyclic adenosine monophosphate responsive element binding protein H (CrebH) as a transcription factor whose messenger RNA can be identified in both the embryonic mouse liver and adult mouse liver and whose expression is dependent on HNF4alpha. Analyses of genomic DNA revealed an HNF4alpha binding site upstream of the CrebH coding sequence that was occupied by HNF4alpha in fetal livers and facilitated transcriptional activation of a reporter gene in transient transfection analyses. Although CrebH is highly expressed during hepatogenesis, CrebH(-/-) mice were viable and healthy and displayed no overt defects in liver formation. However, upon treatment with tunicamycin, which induces an endoplasmic reticulum (ER)-stress response, CrebH(-/-) mice displayed reduced expression of acute phase response proteins. CONCLUSION: These data implicate HNF4alpha in having a role in controlling the acute phase response of the liver induced by ER stress by regulating expression of CrebH.

Download full-text


Available from: Randal J Kaufman,
  • Source
    • "CREB-H target genes strongly overlap with those of OASIS and BBF2H7, including Sec23, Sec24, and extracellular matrix components, but also encompass distinct specific physiological targets in de novo lipogenesis , triglyceride and cholesterol biosynthesis, fatty acid elongation and oxidation, lipolysis, and lipid transport (Lee et al., 2011; Zhang et al., 2012; Barbosa et al., 2013; Xu et al., 2014). CREB-H promotes increased expression and secretion of specific cargoes, including apolipoproteins A I and A IV and phospholipase A 2. Lack of CREB- H expression in the liver results in elevated levels of fatty acids and triglycerides due to the failure to secrete these apolipoproteins and enzyme complexes, which otherwise help suppress plasma levels of these metabolites (Luebke-Wheeler et al., 2008; Lee et al., 2011; Lee, 2012; Zhang et al., 2012). Stimuli including saturated fatty acids , insulin, and an atherogenic high-fat diet promote CREB-H activation , leading to increased target gene transcription (Danno et al., 2010; Gentile et al., 2010; Lee et al., 2010, 2011; Zhang et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CREB‑H, an ER-anchored transcription factor, plays a key role in regulating secretion and in metabolic and inflammatory pathways but how its activity is modulated remains unclear. We examined processing of the nuclear active form and identify a motif around S87 to S90 with homology to DSG type phosphodegrons. We show that this region is subject to multiple phosphorylations which regulate CREB-H stability by targeting it to the SCF(Fbw1a) E3 ubiquitin ligase. Data from phosphatase treatment, use of phosopho-specific antibody and substitution of serine residues, demonstrate phosphorylation of candidate serines in the region, with the core S87/S90 motif representing a critical determinant promoting proteasome-mediated degradation. Candidate kinases CKII and GSK-3b phosphorylate CREB-H in vitro with specificities for different serines. Prior phosphorylation with GSK-3 at one or more of the adjacent serines substantially increases S87/S90-dependent phosphorylation by CKII. In vivo expression of a dominant negative Cul1 enhances steady state levels of CREB‑H, an effect augmented by Fbw1a. CREB-H directly interacts with Fbw1a in a phosphorylation-dependent manner. Finally mutations within the phosphodegron when incorporated into the full length protein, result in increased levels of constitutively cleaved nuclear protein and increased transcription and secretion of a key endogenous target gene, apolipoprotein A IV. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 06/2015; 26(16). DOI:10.1091/mbc.E15-04-0247 · 4.47 Impact Factor
  • Source
    • "Previous reports suggest various nuclear receptors and transcription factors cross talk to regulate the mammalian ER stress response [35]–[36]. In addition, the nuclear receptors GR, PPARα, and HNF4α regulate transcription of the ER bound transcription factor CREBH [15], [36]–[37]. We demonstrated previously that ERRγ regulates ATF6α in response to ER stress [38]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The orphan nuclear receptor estrogen-related receptor-γ (ERRγ) is a constitutively active transcription factor regulating genes involved in several important cellular processes, including hepatic glucose metabolism, alcohol metabolism, and the endoplasmic reticulum (ER) stress response. cAMP responsive element-binding protein H (CREBH) is an ER-bound bZIP family transcription factor that is activated upon ER stress and regulates genes encoding acute-phase proteins whose expression is increased in response to inflammation. Here, we report that ERRγ directly regulates CREBH gene expression in response to ER stress. ERRγ bound to the ERRγ response element (ERRE) in the CREBH promoter. Overexpression of ERRγ by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERRγ or inhibition of ERRγ by ERRγ specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1α was required for ERRγ mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERRγ and PGC1α on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERRγ and PGC1α binding site. Moreover, chronic alcoholic hepatosteatosis, as well as the diabetic obese condition significantly increased CRP gene expression, and this increase was significantly attenuated by GSK5182 treatment. We suggest that orphan nuclear receptor ERRγ directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions.
    PLoS ONE 01/2014; 9(1):e86342. DOI:10.1371/journal.pone.0086342 · 3.23 Impact Factor
  • Source
    • "We also recently reported that orphan nuclear receptor Nur77 is a novel regulator of human APOA5 gene expression [9]. Cyclic AMP response element-binding protein H (CREBH) was identified as a liver-specific bZIP transcription factor [10] [11]. Recent studies have demonstrated that CREBH plays a number of important roles in the hormonal regulation of hepatic gluconeogenesis under fasting or insulin-resistant conditions, as well as in hepatic lipogenesis, fatty acid oxidation, and lipolysis under metabolic stress [12] [13] [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cyclic AMP response element-binding protein H (CREBH) plays important roles in hepatic lipogenesis, fatty acid oxidation, and lipolysis under metabolic stress. Here, we report CREBH as a novel regulator of human APOA5. Knockdown of endogenous CREBH expression via small interfering RNA resulted in the downregulation of human APOA5 mRNA expression in human hepatoma cells, HepG2. Sequence analysis suggested that putative CREBH response element (CREBHRE) is located in the human APOA5 promoter region and is highly conserved in both human and rodent. To clarify whether the human APOA5 promoter is regulated by CREBH, we analyzed the human APOA5 promoter region using a transient transfection assay and determined that transfection of CREBH induced human APOA5 promoter activity. Moreover, it was shown that CREBH directly regulated human APOA5 gene expression by binding to a unique CREBHRE located in the proximal human APOA5 promoter region, using 5'-deletion and mutagenesis of human APOA5 promoter analysis and chromatin immunoprecipitation assay. Taken together, our results demonstrated that human APOA5 is directly regulated by CREBH via CREBHRE and provided a new insight into the role of this liver-specific bZIP transcription factor in lipoprotein metabolism and triglyceride homeostasis.
    07/2013; 2013(6):892491. DOI:10.1155/2013/892491
Show more