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Prenatal caffeine exposure increases the susceptibility to non-alcoholic fatty liver disease in female offspring rats via activation of GR-C/EBPα-SIRT1 pathway.
- Source :
-
Toxicology [Toxicology] 2019 Apr 01; Vol. 417, pp. 23-34. Date of Electronic Publication: 2019 Feb 15. - Publication Year :
- 2019
-
Abstract
- This study aimed to evaluate female adult offspring induced by prenatal caffeine exposure (PCE) are susceptible to non-alcoholic fatty liver disease (NAFLD) and to explore the underlying programming mechanisms. Pregnant rats were intragastrically administered caffeine (30, 60, and 120 mg/kg.d) on gestational day (GD) 9-20. The female adult offspring were randomly divided into three groups: offspring without or with chronic stress during postnatal week (PW) 10-12 and PW28 offspring. Results showed that PW28 PCE female offspring had a higher hepatic triglyceride content and Kleiner scores, accompanied by elevated serum corticosterone levels. Moreover, the expression levels of hepatic glucocorticoid receptor (GR), CCAAT enhancer binding protein α (C/EBPα), fatty acid synthetase (FASN) and the transcription factor-sterol regulatory element binding protein 1c (SREBP1c) were increased, but SIRT1 expression was decreased. The fetal rats and PW12 offspring with chronic stress exhibited similar changes as PW28 offspring, accompanied by increased levels of H3K14ac and H3K27ac in the SREBP1c and FASN gene promoters. These effects were also observed by treating L02 cells with cortisol and were partially reversed by GR or C/EBPα siRNA or treatment with the SIRT1 agonist resveratrol. Taken together, PCE-induced high glucocorticoids levels enhanced histone modifications and expression of SREBP1c and FASN via activation of the GR-C/EBPα-SIRT1 pathway in utero. This enhanced female fetal hepatic triglyceride synthesis and continued throughout postnatal and adult life, increasing the susceptibility to adult NAFLD.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Caffeine administration & dosage
Dose-Response Relationship, Drug
Female
Non-alcoholic Fatty Liver Disease chemically induced
Non-alcoholic Fatty Liver Disease pathology
Pregnancy
Prenatal Exposure Delayed Effects chemically induced
Prenatal Exposure Delayed Effects pathology
Rats
Rats, Wistar
Signal Transduction drug effects
Signal Transduction physiology
CCAAT-Binding Factor metabolism
Caffeine toxicity
Non-alcoholic Fatty Liver Disease metabolism
Prenatal Exposure Delayed Effects metabolism
Receptors, Glucocorticoid metabolism
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3185
- Volume :
- 417
- Database :
- MEDLINE
- Journal :
- Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 30776459
- Full Text :
- https://doi.org/10.1016/j.tox.2019.02.008