Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice

Zhang, Chunbin; Wang, Guohui; Zheng, Ze; Maddipati, Krishna Rao; Zhang, Xuebao; Dyson, Gregory; Williams, Paul J.; Duncan, Stephen A.; Kaufman, Randal J.; Zhang, Kezhong

doi:10.1002/hep.24783

Cited by 167 publications

(238 citation statements)

References 28 publications

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“…Evidence implicates the PPAR␣-RXR␣ heterodimer in regulating lipid metabolism (19), whereas CREBH, independent of PPAR␣, induces a systemic inflammatory response upon ER stress (20). CREBH also modulates lipid metabolism in response to metabolic stress (21). However, the exact function of the PPAR␣-CREBH complex is not known.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Girer

Murray

Omiecinski

et al. 2016

Journal of Biological Chemistry

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The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic The Aryl hydrocarbon receptor (AHR) 2 is a ligand-activated basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) transcription factor, classically known for mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity. AHR normally resides in the cytoplasm, bound to molecules of heat shock protein 90, X-associated protein 2, and p23. Upon agonist (i.e. TCDD) binding, AHR translocates to the nucleus and aryl hydrocarbon receptor nuclear translocator (ARNT) displaces the cytoplasmic complex to form an AHR-ARNT heterodimer. The AHR-ARNT complex is then able to bind dioxin response elements (DRE) in the promoter region of a wide array of genes, many of which are involved in endogenous and xenobiotic metabolism (e.g. CYP1A1, CYP1A2, and CYP1B1) (1).Several lines of evidence indicate that AHR is involved in the regulation of metabolic homeostasis. For example, TCDD activation of AHR alters the expression of various genes involved in hepatic metabolism (2). Additionally, AHR is involved in the regulation of gluconeogenesis via the AHR-responsive gene TCDD-inducible poly(ADP-ribose) polymerase (Tiparp) (3). However, these studies primarily examine the role of AHR in metabolism when activated by TCDD, a xenobiotic compound. Therefore, the physiological role of AHR in metabolic homeostasis remains poorly understood.Recently, there has been keen interest in the potential use of the metabolic hormone fibroblast growth factor 21 (FGF21) as a treatment for obesity. Administration of recombinant FGF21 in various animal models of obesity consistently results in weight loss, fat pad reduction, and improved insulin sensitivity (4, 5). Physiologically, FGF21 is induced by fasting, and acts as an endocrine hormone to induce gluconeogenesis, ketogenesis, and torpor (6). Further evidence shows that these FGF21-mediated responses depend upon direct binding of PPAR␣-RXR␣ to the Fgf21 promoter region to activate transcription (7). PPAR␣, in combination with cAMP-responsive element-binding protein, hepatocyte specific (CREBH), has also been implicated in the activation of Fgf21 expression (8). Alternatively, carbohydrate response element-binding protein (ChREBP) is known to activate Fgf21 expression under hyperglycemic conditions (9). Recent studies suggest that ChREBP-dependent transcription might also be directly involved in the FGF21-mediated control of sweet taste preference and sugar intake (10).* This work was supported by the National Institute of Food and Agriculture, U.S. Dept. of Agriculture award 2014-06624, and National Institutes of Health Grants ES004869 and E...

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Section: Discussionmentioning

confidence: 99%

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Girer

Murray

Omiecinski

et al. 2016

Journal of Biological Chemistry

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“…Creb3l3 (CREBH) is a transcription factor belonging to the cyclic AMP response element binding protein transcription factor (CREB/ATF) family 53) and has been reported to regulate the serum amyloid P-component (SAP) and C-reactive protein (CRP) gene expression in response to systemic inflammatory signaling in the liver 54) . In addition, CREB3l3 was shown to regulate gluconeogenesis via the modulation of the Pepck-c and G6Pase genes 55) as well as many genes involved in hepatic lipid metabolism 56) . Furthermore, others have suggested that Creb3l3 is a direct target of PPAR and that the induction of CREB3l3 is involved in nutritional regulation in the fasting state 57) .…”

Section: Conflicts Of Interestmentioning

confidence: 99%

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Raza-Iqbal

Tanaka

Anai

et al. 2015

J Atheroscler Thromb

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Aim: Selective PPAR modulators (SPPARM ) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARM K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. Methods: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARM on the liver gene expression. Results: Consequently, a cell-based transactivation assay showed that K-877 activates PPAR with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid -oxidative genes in human hepatocytes and the mouse liver. Almost all genes up-or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly

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“…Genetically CREBH-deficient mice showed higher plasma triacylglycerol concentrations than wild-type mice, and this was due to inefficient triacylglycerol clearance catalysed by lipoprotein lipase [25]. More recently, Zhang et al showed that disruption of CREBH activity leads to massive accumulation of hepatic lipid metabolites and significant increases in plasma triacylglycerol levels in animals fed with an atherogenic high-fat diet (HFD) [26]. However, the role of CREBH in controlling insulin-and LXR-stimulated SREBP-1c production and hepatic lipogenesis by a pharmacological lipid-lowering agent remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Min

Jeong

et al. 2012

Diabetologia

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Aims/hypothesis Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis. Methods The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production. Results Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, AdCrebh inhibited insulin-and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo. Conclusions/interpretation These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.

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Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice

Cited by 167 publications

References 28 publications

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

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