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Interactions between nuclear receptors glucocorticoid receptor α and peroxisome proliferator–activated receptor α form a negative feedback loop

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Abstract

Both nuclear receptors glucocorticoid receptor α (GRα) and peroxisome proliferator–activated receptor α (PPARα) are involved in energy and lipid metabolism, and possess anti-inflammation effects. Previous studies indicate that a regulatory loop may exist between them. In vivo and in vitro studies showed that glucocorticoids stimulate hepatic PPARα expression via GRα at the transcriptional level. This stimulation of PPARα by GRα has physiological relevance and PPARα is involved in many glucocorticoid-induced pathophysiological processes, including gluconeogenesis and ketogenesis during fasting, insulin resistance, hypertension and anti-inflammatory effects. PPARα also synergizes with GRα to promote erythroid progenitor self-renewal. As the feedback, PPARα inhibits glucocorticoid actions at pre-receptor and receptor levels. PPARα decreases glucocorticoid production through inhibiting the expression and activity of type-1 11β-hydroxysteroid dehydrogenase, which converts inactive glucocorticoids to active glucocorticoids at local tissues, and also down-regulates hepatic GRα expression, thus forming a complete and negative feedback loop. This negative feedback loop sheds light on prospective multi-drug therapeutic treatments in inflammatory diseases through a combination of glucocorticoids and PPARα agonists. This combination may potentially enhance the anti-inflammatory effects while alleviating side effects on glucose and lipid metabolism due to GRα activation. More investigations are needed to clarify the underlying mechanism and the relevant physiological or pathological significance of this regulatory loop.

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Abbreviations

GRα :

Glucocorticoid receptor α.

PPARα:

Peroxisome proliferator–activated receptor α.

GCs:

Glucocorticoid hormones.

GREs:

glucocorticoid-responsive elements.

3′ UTR:

3′-untranslated region.

hGR:

Human GRα.

mGR:

Mouse GR.

rGR:

Rat GR.

PPREs:

Peroxisome proliferator response elements.

RXR:

Retinoid X receptor.

AP-1:

Activator protein 1.

NF-κB:

Nuclear factor kappa B.

ACO:

Acyl CoA oxidase.

FFA:

Free fatty acid.

NAFLD:

Non-alcoholic fatty liver disease.

HFD:

High fat diet.

DEX:

Dexamethasone.

Epo:

Erythropoietin.

DBA:

Diamond-Blackfan Anemia.

BFU-E:

Burst-forming unit erythroid.

iNOS:

Inducible nitric-oxide synthase.

IBDs:

Inflammatory bowel diseases.

DNBS:

Dinitrobenzene sulfonic acid.

TNF-α:

Tumor necrosis factor.

IL-6:

Interleukin-6.

MCP-1:

Monocyte chemoattractant protein-1.

MMP-9:

Matrix metalloproteinase-9.

HO:

Heme oxygenase.

BVR:

Biliverdin reductase.

UGT:

Uridine diphosphate glucuronyltransferase.

UGT1A1:

UDP-glucuronosyltransferase 1A1.

ECs:

Endothelial cells.

FGF21:

Fibroblast growth factor 21.

IκBα:

NF-κB inhibitor alpha.

i.p:

Intraperitoneal.

11β-HSD1:

Type-1 11β-hydroxysteroid dehydrogenase.

GILZ:

Glucocorticoid-induced leucine zipper.

TG:

Triglyceride.

PEPCK:

Phosphoenolpyruvate carboxykinase.

CRH:

Corticotropin-releasing hormone.

ACTH:

Adrenocorticotropin.

LPL:

Lipoprotein lipase.

RE:

Response element.

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Funding

This study was supported by China Postdoctoral Science Foundation (grant no. 2021M702339 to Y Li) and Health Commission of Sichuan Province (grant no. 21PJ029 to Y Li).

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  1. Laboratory of Endocrinology and Metabolism, Department of Endocrinology, West China Hospital, Sichuan University, 610041, Chengdu, China

    Hongjiao Gao, Yujue Li & Xiang Chen PhD

  2. Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Zunyi Medical University (the First People’s Hospital of Zunyi), 563002, Zunyi, China

    Hongjiao Gao

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Gao, H., Li, Y. & Chen, X. Interactions between nuclear receptors glucocorticoid receptor α and peroxisome proliferator–activated receptor α form a negative feedback loop. Rev Endocr Metab Disord 23, 893–903 (2022). https://doi.org/10.1007/s11154-022-09725-w

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