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Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPAR? Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice.

ABSTRACT: The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs. Pxr^-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16?-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes, mostly xenobiotic-metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor ? (PPAR?) signature. Comparison of this signature with a list of fasting-induced PPAR? target genes confirmed that PXR activation decreased the expression of more than 25 PPAR? target genes, among which was the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPAR? activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis.

SUBMITTER: Barretto SA

PROVIDER: S-EPMC6696478 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice.

Barretto Sharon Ann SA Lasserre Frédéric F Fougerat Anne A Smith Lorraine L Fougeray Tiffany T Lukowicz Céline C Polizzi Arnaud A Smati Sarra S Régnier Marion M Naylies Claire C Bétoulières Colette C Lippi Yannick Y Guillou Hervé H Loiseau Nicolas N Gamet-Payrastre Laurence L Mselli-Lakhal Laila L Ellero-Simatos Sandrine S

International journal of molecular sciences 20190801 15

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs. <i>Pxr</i><sup>-/-</sup> C57Bl6/J male mice treated with the rodent specific ligand ...[more]

PMID: 31374856

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Project description:ObjectiveIncreased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.MethodsWe tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.ResultsHepatic expression of ChREBP-? and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-? and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.ConclusionsIn summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

Dataset Information

Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPAR? Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice.

Publications

Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice.

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