REDUCED OXYGEN TENSION IMPAIRS THE EXPRESSION OF HEPATIC
CHOLESTEROL 7α-HYDROXYLASE (CYP7A1): IMPLICATIONS FOR FETAL
PROGRAMMING
J.E. Osumek1, J.S. Morton2, S.T. Davidge2, and D.B. Hardy1
1
Departments of Ob/Gyn and Physiology & Pharmacology, The Children's Health Research
Institute, The Lawson Health Research Institute, The University of Western Ontario, London,
Ontario N6A 5C1 and 2Perinatal Research Centre, Departments of Obstetrics and Gynecology
and Physiology, University of Alberta, Edmonton, Alberta
High circulating cholesterol is one of the predominant risk factors for adult cardiovascular
disease (CVD). The liver is the major site of cholesterol homeostasis and expresses CYP7A1,
the enzyme involved in the catabolism of cholesterol to bile acids. CYP7A1 deficiency leads to
hypercholesterolemia and a proatherogenic phenotype. Interestingly, epidemiological studies
have indicated that low birthweight (LBW) babies have increased risk of CVD in adulthood.
Moreover, hypoxia in utero has been demonstrated to impair fetal development leading to longterm adaptive changes in the offspring. In pregnant rats exposed to low oxygen (LO) conditions
in pregnancy (12% O2 relative to 20% O2), the offspring are LBW, have decreased liver to
bodyweight ratio, and an increased risk of CVD as adults. Therefore, we hypothesized that
decreased oxygen tension in utero impairs hepatic cholesterol metabolism. Methods and
Results: Using the pregnant LO rat model, it was demonstrated that 4 month LO male offspring
had decreased birthweight relative to control, along with attenuated expression of hepatic
CYP7A1. To further elucidate the molecular mechanisms involved, McArh-7777 rat hepatoma
cells were exposed to decreasing oxygen concentrations (20% to 5% to 1%) for 24 hours. These
cells demonstrated an O2-dependent decrease in CYP7A1 expression, and an associated recovery
in expression with increased O2 concentrations. Moreover, the decrease in oxygen tension was
associated with diminished expression of acetylated Histone H3 (Lysine 9,14), a marker of active
chromatin. Conclusion: Collectively, these results suggest that decreased oxygen tension
exposure may influence the efflux of cholesterol via impaired hepatic CYP7A1 expression.
Sources of Support: Supported by a Sick Kids Foundation/CIHR New Investigator Award, The
Molly Towell Perinatal Research Foundation, and the LHRI Dustin Wighton Award.