Regulation of Hepatic Gluconeogenesis by an ER-Bound Transcription Factor, CREBH

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.
Cell metabolism (Impact Factor: 17.57). 04/2010; 11(4):331-9. DOI: 10.1016/j.cmet.2010.02.016
Source: PubMed


Endoplasmic reticulum (ER)-bound transcription factor families are shown to be involved in the control of various metabolic pathways. Here, we report a critical function of ER-bound transcription factor, CREBH, in the regulation of hepatic gluconeogenesis. Expression of CREBH is markedly induced by fasting or in the insulin-resistant state in rodents in a dexamethasone- and PGC-1alpha-dependent manner, which results in the accumulation of active nuclear form of CREBH (CREBH-N). Overexpression of constitutively active CREBH activates transcription of PEPCK-C or G6Pase by binding to its enhancer site that is distinct from the well-characterized CREB/CRTC2 regulatory sequences in vivo. Of interest, knockdown of CREBH in liver significantly reduces blood glucose levels without altering expression of genes involved in the ER stress signaling cascades in mice. These data suggest a crucial role for CREBH in the regulation of hepatic glucose metabolism in mammals.

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Available from: Dipanjan Chanda, Aug 28, 2015
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    • "We transfected isogenic constructs expressing full-length versions of the wt and mutants and analyzed relative levels of the cleaved products (Figure 9c). Consistent with our previous results (Bailey et al., 2007; Bailey and O'Hare, 2007; Llarena et al., 2010) and those of other laboratories (Danno et al., 2010; Lee et al., 2010; Xu et al., 2014), the full-length wt protein produces some but minor amounts of the cleaved product, again almost all of which is in the N 1 form (Figure 9c, lane 1). Each of the mutants 3S+DSG, DSG, and FIGURE 8: The GSK-3 inhibitor CHIR99021 increases the abundance of CREB-HΔTMC. "
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    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.
    Full-text · Article · Jun 2015 · Molecular biology of the cell
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    • "The data also allowed us to conclude that during fasting, only a small quantity of pyruvate is directed toward the generation of GLY-TAG (1/20 to glucose) in the liver of both the C and LPHC animals. Other studies (Cassuto et al. 2005; Hall et al. 2007; Lee et al. 2010) have indicated that corticosterone, a glucocorticoid hormone found in high levels in the blood of LPHC animals (Dos Santos et al. 2012), inhibits the transcription of the PEPCK gene in adipose tissue but stimulates it in the liver and renal cortex (Meisner et al. Fig. 4. Protein levels of PEPCK and GyK in the livers of fasted rats (15 h) previously fed a control diet (C) or a low-protein, high-carbohydrate diet (LPHC) for 15 days. "
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    ABSTRACT: The our objective was to investigate the adaptations induced by a low-protein, high-carbohydrate (LPHC) diet in growing rats, which by comparison with the rats fed a control (C) diet at displayed lower fasting glycemia and similar fasting insulinemia, despite impairment in insulin signaling in adipose tissues. In the insulin tolerance test the LPHC rats showed higher rates of glucose disappearance (30%) and higher tolerance to overload of glucose than C rats. The glucose uptake by the soleus muscle, evaluated in vivo by administration of 2-deoxy-[(14)C]glucose, increased by 81%. The phosphoenolpyruvate carboxykinase content and the incorporation of [1-(14)C]pyruvate into glucose was also higher in the slices of liver from the LPHC rats than in those from C rats. The LPHC rats showed increases in l-lactate as well as in other gluconeogenic precursors in the blood. These rats also had a higher hepatic production of glucose, evaluated by in situ perfusion. The data obtained indicate that the main substrates for gluconeogenesis in the LPHC rats are l-lactate and glycerol. Thus, we concluded that the fasting glycemia in the LPHC animals was maintained mainly by increases in the hepatic gluconeogenesis from glycerol and l-lactate, compensating, at least in part, for the higher glucose uptake by the tissues.
    Full-text · Article · Apr 2014 · Canadian Journal of Physiology and Pharmacology
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    • "In addition, CREBH is a master regulator of the lipin 1 gene, a key regulator of lipid metabolism [17]. Both CREBH and ERRγ gene expression is enhanced in a diabetic mouse model to increase blood glucose level [15], [6]. Regulation of both factors is important to regulate gluconeogenesis in response to ER stress, and diabetes. "
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    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.
    Full-text · Article · Jan 2014 · PLoS ONE
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