Role of hepatic cytochrome P450 oxidoreductase in bone development (921.1)

Abstract

Cytochrome P450 oxidoreductase (POR) is the only known electron donor for Cytochromes P450 (CYPs), heme oxygenase (HO), and dehydrocholesterol reductase in the endoplasmic reticulum (ER). Hepatic CYPs are essential for the metabolism of cholesterol, steroids, sex hormones, and xenobiotics, such as drugs and toxins. Thus, alterations in POR activity will have multiple effects on the physiological activity of multitudinous metabolites. Human mutations in POR have been reported and present as altered steroidogenic profiles, severe craniofacial and bone defects resembling Antley‐Bixler syndrome (ABS). Liver‐specific POR null (LCN) mice were examined to study endo‐ and xeno‐biotic metabolism. Surprisingly, previous studies demonstrated only minor changes in plasma and intestinal lipid content of LCN mice, suggesting that lipid homeostasis is maintained despite significant hepatic steatosis. Here, we show for the first time that the deletion of POR from the liver leads to decreased bone volume in both cortical and trabecular compartments, as measured by micro computed tomography analysis, but no notable skull defects. In bone‐specific POR null mice, however, we have previously observed defects in skull morphology and trabecular bone density. This difference suggests that the action of hepatic CYP‐derived circulating metabolites is critical for normal bone development and is distinct from bone‐ specific CYP activity. There are several potentially important metabolites that could affect bone homeostasis and require hepatic CYP hydroxylation such as vitamin D, retinoic acid and steroid hormones. These data highlight the importance of both systemic and local POR activity in healthy bone development.Grant Funding Source: Supported by NIH grant GM081568 to BSSM and SPP