PMID- 30825513
OWN - NLM
STAT- MEDLINE
DCOM- 20200406
LR  - 20200408
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 418
DP  - 2019 Apr 15
TI  - Caffeine programs hepatic SIRT1-related cholesterol synthesis and 
      hypercholesterolemia via A2AR/cAMP/PKA pathway in adult male offspring rats.
PG  - 11-21
LID - S0300-483X(18)30247-6 [pii]
LID - 10.1016/j.tox.2019.02.015 [doi]
AB  - Clinical and animal studies have indicated that hypercholesterolemia has 
      intrauterine developmental origin. Our previous studies showed that prenatal 
      caffeine exposure (PCE) increased the serum total cholesterol (TCH) levels in 
      adult offspring rats. This study investigates the intrauterine programming 
      mechanism of PCE male offspring rats susceptible to adult hypercholesterolemia. 
      Pregnant Wistar rats were intragastrically administered caffeine (30, 60, and 
      120 mg/kg∙d) from gestational days (GD) 9 to 20. Male offspring were sacrificed 
      under anesthesia at GD20 and postnatal week (PW) 12, and the serum and liver were 
      collected. The effects of caffeine (0-100 muM, 24 h) on the expression of 
      cholesterol synthesis related genes and their epigenetic mechanisms were 
      confirmed in L02 cells. The results showed that PCE induced higher levels of 
      serum TCH, LDL-C and higher ratios of TCH/HDL-C and LDL-C/HDL-C. Furthermore, the 
      high levels of histone acetylation (via H3K14ac and H3K27ac) and the expression 
      of genes (Srebf2, Hmgcr, Hmgcs1) were responsible for cholesterol synthesis. The 
      results of PCE offspring in utero and the data in vitro exhibited similar 
      changes, and accompanied by the reduced expression of adenosine A2A receptor 
      (A2AR), cyclic adenosine monophosphate (cAMP), sirtuin1 and protein kinase A 
      (PKA). These changes could be reversed by A2AR agonist (CGS-21680), cAMP agonist 
      (forskolin) and sirtuin1 agonist (resveratrol). Therefore, our results confirmed 
      that caffeine could enhance histone acetylation and expression levels of genes 
      responsible for cholesterol synthesis via inhibiting the A2AR/cAMP/PKA pathway 
      and down-regulating sirtuin1, which continued throughout adulthood and elevated 
      hepatic cholesterol synthesis and hypercholesterolemia in the male offspring 
      rats.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Hu, Shuwei
AU  - Hu S
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China.
FAU - Liu, Kexin
AU  - Liu K
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China.
FAU - Luo, Hanwen
AU  - Luo H
AD  - Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan 430071, China.
FAU - Xu, Dan
AU  - Xu D
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan 430071, China.
FAU - Chen, Liaobin
AU  - Chen L
AD  - Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan 430071, China.
FAU - Zhang, Li
AU  - Zhang L
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan 430071, China. Electronic address: alicedoupont@163.com.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan 430071, China. Electronic address: wanghui19@whu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190227
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Histones)
RN  - 0 (Receptor, Adenosine A2A)
RN  - 3G6A5W338E (Caffeine)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 3.5.1.- (Sirt1 protein, rat)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - Acetylation
MH  - Age Factors
MH  - Animals
MH  - Caffeine/*toxicity
MH  - Cell Line
MH  - Cholesterol/*biosynthesis/blood
MH  - Cyclic AMP/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - DNA Methylation/drug effects
MH  - Epigenesis, Genetic/drug effects
MH  - Female
MH  - Gene Expression Regulation, Enzymologic
MH  - Gestational Age
MH  - Histones/metabolism
MH  - Hypercholesterolemia/blood/*chemically induced/enzymology/genetics
MH  - Liver/*drug effects/enzymology
MH  - Male
MH  - Maternal Exposure/adverse effects
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Rats, Wistar
MH  - Receptor, Adenosine A2A/*metabolism
MH  - Second Messenger Systems
MH  - Sirtuin 1/*metabolism
OTO - NOTNLM
OT  - Caffeine
OT  - Hepatic cholesterol synthesis
OT  - Histone acetylation
OT  - Hypercholesterolemia
EDAT- 2019/03/03 06:00
MHDA- 2020/04/09 06:00
CRDT- 2019/03/03 06:00
PHST- 2018/08/15 00:00 [received]
PHST- 2019/01/30 00:00 [revised]
PHST- 2019/02/25 00:00 [accepted]
PHST- 2019/03/03 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/03/03 06:00 [entrez]
AID - S0300-483X(18)30247-6 [pii]
AID - 10.1016/j.tox.2019.02.015 [doi]
PST - ppublish
SO  - Toxicology. 2019 Apr 15;418:11-21. doi: 10.1016/j.tox.2019.02.015. Epub 2019 Feb 
      27.