Journal
CELL REPORTS
Volume 21, Issue 2, Pages 403-416Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.065
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Funding
- Region Occitanie
- Lee Kong Chian School of Medicine, Nanyang Technological University
- ChroME Network (Marie Curie Sklodowska Action) [H2020-MSCA-ITN-2015-675610]
- Foundation for the Medical Research (FRM) [DEQ20150331744]
- European Foundation for the Study of Diabetes (EFSD) Novonordisk
- National Agency for Research (ANR) [ANR-12BSV1-0025-ObeLiP, ANR-15-CE14-0026-Hepatokind]
- European Research Council [ERC-2013-StG-336629]
- city of Paris
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While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor alpha (PPAR alpha), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp(-/-) mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp(-/-) mice. Unexpectedly, carbohydrate challenge of hepatic Ppar alpha knockout mice also demonstrated aPPAR alpha-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPAR alpha. Our study reports that PPAR alpha is required for the ChREBP-induced glucose response of FGF21.
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