Abstract 18019: Activation of Hepatic Hif-2a Signaling Perturbs Cholesterol Homeostasis in Mice
Cardiovascular disease (CVD) is the leading cause of death in the United States. Therefore, identifying novel pathways involved in the pathogenesis of CVD becomes imperative. Inflammation and hypercholesterolemia are the two hallmarks of CVD. Patients with chronic intermittent hypoxia or obstructive sleep apnea are at high risk for CVD due to aberrant cholesterol levels. Evolutionarily, cholesterol synthesis is a highly oxygen and energy dependent process. Therefore, the molecular mechanism involved in the paradoxical increase in cholesterol during hypoxia remains unclear. Hypoxia signaling is mediated through a well-conserved hypoxia driven transcription factors, hypoxia-inducible factor (HIF)-1 and HIF-2. Mice with a liver-specific disruption of the Von Hippel Lindau protein (VhlLivKO), a critical E3 ubiquitin ligase that degrades HIFs, exhibit increased levels of HIF-1 and HIF-2 protein and develop hepatic steatosis, systemic inflammation, hypercholesterolemia and have decreased survival. Moreover, we show that the transcription factor hypoxia-inducible factor (HIF)-2 is highly activated in the liver of rodent models of atherogenesis. Activation of HIF-2 in liver disrupts the circadian expression of cholesterol hydroxylases leading to hypercholesterolemia. Using a comprehensive metabolomic analysis, we identified an arginine metabolite, asymmetric dimethylarginine (ADMA) is highly induced in the serum and liver of C57BL/6 mice fed with high cholesterol diet. ADMA potently activates HIF-2 in human hepatoma HepG2 and colon-derived SW-480 cells. Our results demonstrate that metabolite induced HIF-2 signaling in liver perturbs cholesterol homeostasis leading to systemic inflammation and hypercholesterolemia.
Author Disclosures: S.K. Ramakrishnan: None.
- © 2015 by American Heart Association, Inc.