Effect of deficiency in SREBP cleavage-activating protein on lipid metabolism during intermittent hypoxia.
Obstructive sleep apnea (OSA), a condition leading to intermittent hypoxia (IH) during sleep, has been associated with dyslipidemia, atherosclerosis, and increased cardiovascular mortality. We previously showed in C57BL/6J mice that IH causes hypercholesterolemia and upregulation of sterol regulatory element binding protein (SREBP)-1, a transcription factor of lipid biosynthesis in the liver. The goal of the present study was to provide mechanistic evidence that IH causes hypercholesterolemia via the SREBP-1 pathway. We utilized mice with a conditional knockout of SREBP cleavage-activating protein (SCAP) in the liver (L-Scap- mice), which exhibit low levels of an active nuclear isoform of SREBP-1 (nSREBP-1). We exposed L-Scap- mice and wild-type (WT) littermates to IH or intermittent air control for 5 days. IH was induced during the 12-h light phase by decreasing Fi(O(2)) from 20.9% to 5% for a period of 30 s with rapid reoxygenation to 20.9% through the subsequent 30 s. In WT mice, IH increased fasting levels of serum total and HDL cholesterol, serum triglycerides, serum and liver phospholipids, mRNA levels of SREBP-1 and mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), and protein levels of SCAP, nSREBP-1, and mtGPAT in the liver. In L-Scap- mice, IH did not have any effect on serum and liver lipids, and expression of lipid metabolic genes was not altered. We conclude that hyperlipidemia in response to IH is mediated via the SREBP-1 pathway. Our data suggest that the SREBP-1 pathway could be used as a therapeutic target in patients with both OSA and hyperlipidemia.
Li
Jianguo
J
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nanayakkara
Ashika
A
Jun
Jonathan
J
Savransky
Vladimir
V
Polotsky
Vsevolod Y
VY
D000818:Animals; D001273:Atmosphere Exposure Chambers; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005215:Fasting / Q000097:blood; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012008:Recurrence; D015398:Signal Transduction / Q000502:physiology; D020181:Sleep Apnea, Obstructive / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C102196:SREBP cleavage-activating protein; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D005992:Glycerol-3-Phosphate O-Acyltransferase