Dataset Information

Nutrient-sensing nuclear receptors PPAR? and FXR control liver energy balance.

ABSTRACT: The nuclear receptors PPAR? (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPAR? activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPAR? but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPAR?, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPAR? and FXR are dysregulated in chronic undernutrition. We conclude that PPAR? and FXR function coordinately to integrate liver energy balance.

SUBMITTER: Preidis GA

PROVIDER: S-EPMC5373864 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

Preidis Geoffrey A GA Kim Kang Ho KH Moore David D DD

The Journal of clinical investigation 20170313 4

The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogen ...[more]

PMID: 28287408

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Project description:Liver dysfunction, including coagulopathy, is a prominent feature of protein-energy malnutrition. To identify mechanisms underlying malnutrition-associated coagulopathy, we administered a low-protein low-fat diet to lactating dams and examined hepatic transcription and plasma coagulation parameters in young adult weanlings. Malnutrition impacted body composition to a greater extent in male versus female mice. Transcriptional profiles suggested opposing effects of nutrient-sensing nuclear receptors, namely induction of peroxisome proliferator-activated receptor α (PPARα) targets and repression of farnesoid-X-receptor (FXR) targets. Coagulopathy with decreased synthesis of fibrinogen-α (FGA) and factor 11 (F11) was observed in malnourished male animals but not female animals. In primary mouse hepatocytes, FXR agonist increased and PPARα agonist decreased Fga and F11 messenger RNA expression. Nuclear receptor DNA response elements were identified in the Fga and F11 gene regulatory regions, and opposing effects of FXR and PPARα were confirmed with luciferase assays. Unexpectedly, hepatic PPARα protein was markedly depleted in malnourished male liver and was not enriched on Fga or F11 response elements. Rather, there was loss of FXR binding at these response elements. Reduced PPARα protein was associated with loss of hepatocyte peroxisomes, which are necessary for bile acid biosynthesis, and with decreased concentrations of bile acids that function as FXR ligands, most notably the FXR agonist chenodeoxycholic acid. Conclusion: Malnutrition impairs growth and liver synthetic function more severely in male mice than in female mice. Malnourished male mice are coagulopathic and exhibit decreased hepatocyte peroxisomes, FXR agonist bile acids, FXR binding on Fga and F11 gene regulatory elements, and coagulation factor synthesis. These effects are absent in female mice, which have low baseline levels of PPARα, suggesting that nutrient-sensing nuclear receptors regulate coagulation factor synthesis in response to host nutritional status in a sex-specific manner.

Dataset Information

Nutrient-sensing nuclear receptors PPAR? and FXR control liver energy balance.

Publications

Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

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