Liver-Enriched Transcription Factor CREBH Interacts With Peroxisome Proliferator-Activated Receptor α to Regulate Metabolic Hormone FGF21

Kim, Hyun Bae; Méndez, Roberto; Zheng, Ze; Chang, Lin; Cai, Juan; Zhang, Ren; Zhang, Kezhong

doi:10.1210/en.2013-1490

Cited by 113 publications

(165 citation statements)

References 29 publications

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“…In agreement with recent data (12), our results suggest that AHR can bind directly to the Fgf21 promoter at the same location to which the PPAR␣-RXR␣ and PPAR␣-CREBH heterodimers bind (7,8). 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).…”

Section: Discussionsupporting

confidence: 92%

“…Utilizing EMSA, we show that the ChREBP-MLX complex does bind to the proximal Fgf21 ChoRE (Fig. 2B, lanes [5][6][7][8]. Also shown is ChREBP-MLX complex formation with a positive control oligonucleotide containing a consensus ChoRE (Fig.…”

Section: Crementioning

confidence: 83%

“…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).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 92%

Section: Crementioning

confidence: 83%

mentioning

confidence: 99%

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Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Girer

Murray

Omiecinski

et al. 2016

Journal of Biological Chemistry

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“…Several reports have indicated that FGF21 reduces the fasting plasma glucose, TG, insulin and glucagon levels in diabetic rhesus monkeys, indicating the potential for efficacy in humans 39,40) . Although FGF21 has been reported to be a direct PPAR target gene 41,42) , recent work indicates that CREBH 43) and HMGCS2 35) are also involved in the FGF21 gene expression. In this study, CREBH (Supplementary fatty acid -oxidative genes (ACSLs, CPT1A, CPT2, ACADVL, HADHA, HADHB, ACAA2) expression in human hepatocytes.…”

Section: K-877 Regulates the Gene Expression As A Spparmmentioning

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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“…FGF21 was initially described as a protein induced in the liver to control metabolic adaptation to long periods of starvation. This mRNA induction goes through the PPARa [13,73,74] and CREBH [75,76]. Later, several studies showed that FGF21 expression is regulated not only by fasting but also by other nutritional states [77].…”

Section: Fgf21 Expression Is Regulated By Nutrition Fasting and Feedingmentioning

confidence: 99%

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Pérez-Martí

Sandoval

Marrero

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21-KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

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Liver-Enriched Transcription Factor CREBH Interacts With Peroxisome Proliferator-Activated Receptor α to Regulate Metabolic Hormone FGF21

Cited by 113 publications

References 29 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

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

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