Down-regulation of bile acid synthesis and a metabolic co-activator under hypoxic conditions - implications in obstructive sleep apnea.
Obstructive sleep apnea is characterized by episodes of intermittent hypoxia that occur while the afflicted person sleeps, and is believed to affect and have a negative impact on many people worldwide. Both observational evidence in obstructive sleep apnea patients and direct studies in mice mimicking the disease strongly support an increased risk for atherosclerosis in these groups. Studies to date on atherosclerosis in obstructive sleep apnea have been focused on cholesterol synthesis. However, dysregulation of bile acid synthesis, which is an important means of cholesterol removal, has not been considered in any sleep disorder model to date. While the relationship between hypoxia and bile acid regulation has been explored in a variety of models, no unifying theory currently ties in the pathologic effect of intermittent hypoxia on bile acid regulation in humans or animals. The goal of this article is to propose the role intermittent hypoxia plays in disrupting bile acid synthesis in patients with obstructive sleep apnea, and its metabolic consequences. Reviewed and discussed are the complex interactions of several key molecular players known to be involved in metabolism with emphasis on the principle bile acid synthesis enzyme, cholesterol 7-alpha-hydroxylase, which is proposed to have reduced activity under hypoxic conditions. Furthermore, the metabolic consequences of reduced levels of active peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) under hypoxia, and hypothetically in obstructive sleep apnea, are explored. A better molecular understanding of bile acid synthesis and metabolic dysregulation in this context will hopefully promote the study of new targets in human sleep apneas, and encourage clinical trials using existing therapeutic and dietary interventions in patients afflicted with these conditions.
Johnson
Paul R
PR
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Donald Baxter Building, Room 105, 570 South Preston Street, Louisville, KY 40202, United States. paul.johnson@louisville.edu
D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015536:Down-Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008962:Models, Theoretical; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012891:Sleep Apnea Syndromes / Q000378:metabolism / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism
D001647:Bile Acids and Salts; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System