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Maternal Chronic Intermittent Hypoxia During Gestation Programs Hypercholesterolemia in the Offspring
Author(s) -
Ciriello John,
Iqbal Waseem,
Hardy Daniel
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1247.14
Subject(s) - offspring , endocrinology , medicine , cholesterol 7 alpha hydroxylase , gestation , pregnancy , cholesterol , biology , liver x receptor , ldl receptor , lipoprotein , nuclear receptor , biochemistry , genetics , gene , transcription factor
Chronic intermittent hypoxia (CIH) is the underlying pathophysiological condition seen in individuals with obstructive sleep apnea. We have recently demonstrated that offspring exposed to maternal CIH during pregnancy exhibit reduced Liver X Receptor (LXR) protein leading to augmented expression of hepatic enzymes promoting gluconeogenesis. As LXR also plays an important role in cholesterol homeostasis, this study was done to determine the impact of diminished LXR expression on cholesterol handling by the liver in the offspring of CIH exposed pregnant mothers. Pregnant female Sprague‐Dawley rats were exposed daily to CIH (6.5% nadir; 18 cycles/h; 8h/day) from gestational day‐1 to day‐20. Control mothers were exposed to room air during pregnancy. Offspring were sacrificed at postnatal 6 and 12 weeks of age to assess early life and long‐term alterations in liver function. At both ages, male CIH offspring had significantly (p<0.05) higher total circulating cholesterol levels concomitant with significantly (p<0.05) greater body fat deposition compared to offspring exposed to gestational normoxia. Western blot analysis revealed that adult male CIH offspring at both ages had significantly (p<0.05) lower protein expression of the cholesterol catabolizing enzyme cholesterol 7α‐hydroxylase (CYP7A1), the cholesterol efflux transporter ATP‐binding cassette transporter G8 (ABCG8), and the low density lipoprotein receptor (LDLR) compared to the offspring exposed to gestational normoxia. Taken together, these data indicate that gestational CIH‐induced hypercholesterolemia in the offspring results from diminished expression of LXR target genes associated with cholesterol breakdown, excretion, and removal from the circulation. Support or Funding Information Supported in part by HSFO and CIHR