Aryl hydrocarbon receptor-fibroblast growth factor 21 dissociation of fatty liver from insulin resistance: A timely matter?

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor highly expressed in hepatocytes. Researchers have employed global and liver-specific conditional Ahr knockout mouse models to characterize the physiological roles of the AHR; however, the gestational timing of AHR loss in these models can complicate efforts to distinguish the direct and indirect effects of post-gestational AHR deficiency. Utilizing a novel tamoxifen-inducible AHR knockout mouse model, we analyzed the effects of hepatocyte-targeted AHR loss in adult mice. The data demonstrate that AHR deficiency significantly reduces weight gain and adiposity, and increases multilocular lipid droplet formation within perigonadal white adipose tissue (gWAT). Protein and mRNA expression of fibroblast growth factor 21 (FGF21), an important hepatokine that activates thermogenesis in brown adipose tissue (BAT) and gWAT, significantly increases upon AHR loss and correlates with a significant increase of BAT and gWAT respiratory capacity. Confirming the role of FGF21 in mediating these effects, this phenotype is reversed in mice concomitantly lacking AHR and FGF21 expression. Chromatin immunoprecipitation analyses suggest that the AHR may constitutively suppress Fgf21 transcription through binding to a newly identified xenobiotic response element within the Fgf21 promoter. The data demonstrate an important AHR-FGF21 regulatory axis that influences adipose biology and may represent a “druggable” therapeutic target for obesity and its related metabolic disorders.

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Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m116.715151 ◽

2016 ◽

Vol 291 (29) ◽

pp. 15378-15387 ◽

Cited By ~ 22

Author(s):

Nathaniel G. Girer ◽

Iain A. Murray ◽

Curtis J. Omiecinski ◽

Gary H. Perdew

Keyword(s):

Growth Factor ◽

Aryl Hydrocarbon Receptor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Aryl Hydrocarbon

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Is Trimming the Fat Enough? Fibroblast Growth Factor 21 as An Emerging Treatment for Nonalcoholic Fatty Liver Disease

Hepatology ◽

10.1002/hep.30789 ◽

2019 ◽

Vol 70 (5) ◽

pp. 1860-1862 ◽

Cited By ~ 2

Author(s):

Jody Dushay ◽

Michelle Lai

Keyword(s):

Liver Disease ◽

Growth Factor ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fibroblast Growth Factor ◽

Fatty Liver Disease ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Nonalcoholic Fatty Liver

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The Relation Between Fibroblast Growth Factor 21 and Insulin Resistance in hyperlipidemia Patients

Egyptian Journal of Chemistry ◽

10.21608/ejchem.2021.80062.3947 ◽

2021 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

Rana F. Jasim ◽

Safaa S. Mohammad ◽

Thikra A. Allwsh

Keyword(s):

Insulin Resistance ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth

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Effect of vanillic acid and exercise training on fatty liver and insulin resistance in rats: Possible role of fibroblast growth factor 21 and autophagy

Physiology International ◽

10.1556/2060.2021.00188 ◽

2021 ◽

Keyword(s):

Growth Factor ◽

Fatty Liver ◽

Fibroblast Growth Factor ◽

Vanillic Acid ◽

High Fat Diet ◽

Male Rats ◽

Swimming Exercise ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

High Fat

Abstract Background and aims The prevalence of non-alcoholic fatty liver disease has been alarmingly increased with no lines of effective treatment. Vanillic acid is a naturally occurring polyphenol with promising therapeutic effects. Exercise is well known to be an effective tool against obesity and its consequences. Thus, we aim to study the effect of vanillic acid alone and along with exercise on fatty liver induced by a high-fat diet in a rat model and to investigate possible novel mechanisms involved in their action. Methods In this study, 40 male rats were divided equally into five groups: control (standard chow diet), HFD (high-fat diet), HFD+VA (HFD+ vanillic acid (50 mg/kg/day orally), HFD+EX (HFD+ swimming exercise 5 days/week), HFD+VA+EX (HFD+ vanillic acid+ swimming exercise) for eight weeks. Results Body mass, liver weight, liver enzymes, cholesterol, and triglycerides were significantly decreased in the combined VA+EX group, with marked improvement in hyperglycemia, hyperinsulinemia, and consequently HOMA-IR index compared to the HFD group. These improvements were also reflected in the pathological view. VA and swimming, either solely or in combination, markedly increased hepatic and circulating fibroblast growth factor 21. Additionally, VA and swimming increased the immunohistochemical expression of the autophagosomal marker LC3 and decreased the expression of P62, which is selectively degraded during autophagy. Conclusions These results suggest the hepatoprotective effect of VA and swimming exercise against fatty liver and the involvement of FGF21 and autophagy in their effect.

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Fibroblast growth factor 21 in non-alcoholic fatty liver disease

Metabolism ◽

10.1016/j.metabol.2019.153994 ◽

2019 ◽

Vol 101 ◽

pp. 153994 ◽

Cited By ~ 13

Author(s):

Bradley Tucker ◽

Huating Li ◽

Xiaoxue Long ◽

Kerry-Anne Rye ◽

Kwok Leung Ong

Keyword(s):

Liver Disease ◽

Growth Factor ◽

Fatty Liver ◽

Fibroblast Growth Factor ◽

Fatty Liver Disease ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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Effect of Fibroblast Growth Factor 21 on the Development of Atheromatous Plaque and Lipid Metabolic Profiles in an Atherosclerosis-Prone Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21186836 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6836

Author(s):

Hyo Jin Maeng ◽

Gha Young Lee ◽

Jae Hyun Bae ◽

Soo Lim

Keyword(s):

Insulin Resistance ◽

Growth Factor ◽

Aortic Arch ◽

Fibroblast Growth Factor ◽

Cell Size ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Plaque Size ◽

Fat Cell ◽

Fat Cell Size

Fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism. We aimed to investigate the effect of an FGF21 analogue (LY2405319) on the development of atherosclerosis and its associated parameters. ApoE−/− mice were fed an atherogenic diet for 14 weeks and were randomly assigned to control (saline) or FGF21 (0.1 mg/kg) treatment group (n = 10/group) for 5 weeks. Plaque size in the aortic arch/valve areas and cardiovascular risk markers were evaluated in blood and tissues. The effects of FGF21 on various atherogenesis-related pathways were also assessed. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the FGF21 group than in controls after treatment. FGF21 significantly decreased body weight and glucose concentrations, and increased circulating adiponectin levels. FGF21 treatment alleviated insulin resistance and decreased circulating concentrations of triglycerides, which were significantly correlated with plaque size. FGF21 treatment reduced lipid droplets in the liver and decreased fat cell size and inflammatory cell infiltration in the abdominal visceral fat compared with the control group. The monocyte chemoattractant protein-1 levels were decreased and β-hydroxybutyrate levels were increased by FGF21 treatment. Uncoupling protein 1 expression in subcutaneous fat was greater and fat cell size in brown fat was smaller in the FGF21 group compared with controls. Administration of FGF21 showed anti-atherosclerotic effects in atherosclerosis-prone mice and exerted beneficial effects on critical atherosclerosis pathways. Improvements in inflammation and insulin resistance seem to be mechanisms involved in the mitigation of atherosclerosis by FGF21 therapy.

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