IDENTIFICATION OF THE TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS
ASSOCIATED WITH IMPAIRED EXPRESSION OF HEPATIC CHOLESTEROL 7αHYDROXYLASE (CYP7A1) IN THE OFFSPRING OF MATERNAL PROTEIN
RESTRICTED (MPR) RATS.
G. Sohi1, K. Marchand1, V. Yang1, E. Arany2 and D.B. Hardy1.
1
Departments of Obstetrics & Gynaecology and Physiology & Pharmacology, The Children's
Health Research Institute, The Lawson Health Research Institute, The University of Western
Ontario, London, Ontario, Canada, N6A 5C1 and 2Department of Pathology, Lawson Health
Research Institute, The University of Western Ontario, London, Ontario, Canada.
High circulating cholesterol remains one of the main risk factors for adult cardiovascular disease
(CVD). The major site for the regulation of cholesterol homeostasis occurs in the liver, mainly
through the catabolism of cholesterol via the enzyme CYP7A1, which is under the regulation of
the nuclear Liver X Receptor (LXR). Emerging evidence also suggests that CVD is also
inversely related to birth weight. In rats, maternal protein restriction (MPR) results in offspring
with reduced birthweight and impaired postnatal growth. Therefore, we hypothesized that MPR
may also be associated with abnormal cholesterol catabolism in the offspring via altered
expression of CYP7A1. Methods and Results: In MPR offspring at postnatal day 21, there was a
significant increase in circulating cholesterol. Moreover, Q-RT-PCR and Western Blot analysis
revealed reduced hepatic CYP7A1 expression at postnatal day 21 and day 130. Chromatin
Immunoprecipitation (ChIP) was then employed to determine if any in vivo changes in LXR
binding and/or posttranslational histone modifications occur to the promoter region of hepatic
CYP7A1. A decrease in hepatic LXR binding at the LXRE (-74/-53 bp) in the promoter of
CYP7A1 in MPR day 130 male offspring was observed. This decrease was accompanied by
diminished acetylation of Histone H3 (K9,14), a mark of active chromatin. Moreover, increased
trimethylation of Histone H3 (K9), associated with closed chromatin, was observed at the same
LXRE. Conclusions: These findings suggest that increased cholesterol in the MPR male
offspring may be due in part to both transcriptional and epigenetic changes in the expression of
CYP7A1.
Sources of Support: Supported by a Department of Obstetrics and Gynaecology Graduate
Scholarship, the Sick Kids Foundation/CIHR New Investigator Award and the Molly Towell
Perinatal Research Foundation.