Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

Cheng, Xinjian; Vispute, Saurabh; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D.

doi:10.1016/j.taap.2014.04.013

Cited by 33 publications

(37 citation statements)

References 35 publications

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“…Fgf21 mRNA was induced 17.2-and 6.2-fold at 28 and 92 days, respectively. No AhR enrichment as observed, unlike previous reports (Cheng et al, 2014;Girer et al, 2016) that could be accounted for by differences in treatment duration and model.…”

Section: Altered Glucose and Glycogen Metabolismcontrasting

confidence: 87%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 mg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1b, -2, -4, -6, and -10, as well as TNF-a and IFN-c, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNASeq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

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Section: Altered Glucose and Glycogen Metabolismcontrasting

confidence: 87%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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“…We further speculate that AHR may modulate the cellular response to ER stress, given the ability of agonist-stimulated AHR to attenuate potent ER stress-driven Fgf21 expression in cell culture experiments. Ultimately, the physiological role of AHR in attenuating Fgf21 expression presented here contrasts with the ability of high-dose TCDD exposure to increase Fgf21, as others have observed (12,13). Therefore, additional research is required to fully understand the intricate role of AHR in Fgf21 expression.…”

Section: Discussionmentioning

confidence: 69%

“…In summary, Fgf21 is involved with several biological processes, and is therefore subject to complex regulatory control. Recent studies have indicated that AHR can increase hepatic Fgf21 expression in the presence of TCDD (12). Similarly, a separate study revealed elevated Fgf21 expression in mice expressing a constitutively active form of AHR in the liver (13).…”

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confidence: 89%

“…However, data from the former study indicate that hepatic Fgf21 expression is also greater in Ahr Ϫ/Ϫ mice compared with Ahr ϩ/ϩ mice. Furthermore, their data demonstrate that activation of AHR with relatively low doses of TCDD represses hepatic Fgf21 expression over time (12). Such contradicting results warrant further investigation into the role of AHR in regulating Fgf21 mRNA.…”

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confidence: 98%

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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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“…FGF21 can improve deteriorated metabolic variables in obese diabetic humans and in animal models of obesity and diabetes [4][5][6][7]. In addition, FGF21 plays a protective role in toxin-induced tissue injury [8,9]. Protein folding occurs in the endoplasmic reticulum (ER).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress

Kim

et al. 2014

Diabetologia

102

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Aims/hypothesis Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity.Methods Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. Results We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinaseeukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. Conclusions/interpretation Our results suggest that FGF21 plays an important role in the adaptive response to ER stress-or obesity-induced hepatic metabolic stress.

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Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

Cited by 33 publications

References 35 publications

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress

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