Effect of deficiency in SREBP cleavage-activating protein on lipid metabolism during intermittent hypoxia

Abstract

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.

Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

“…Why does acute hypoxia decrease VLDL secretion while chronic IH apparently augments it (39)? Perhaps the chronicity of hypoxia or intervening periods of normoxic recovery provides an opportunity for transcriptional upregulation of genes involved in lipid synthesis and secretion (38). Normoxic mice in the previous study were also food restricted (39) to match the CO2 was collected at 10-min intervals for 1 h to assess relative rates of whole body ␤-oxidation.…”

Nocturnal Intermittent Hypoxia and Metabolic Syndrome; the Effect of being Overweight: the CIRCS Study

“…Activation of the hypothalamic-pituitaryadrenal axis increased serum cortisol levels 28) , leading to hyperglycemia and insulin resistance 29) . Lastly, an experimental study has shown that intermittent hypoxia caused an increase in hepatic levels of triglyceride and phospholipid, and upregulated the expression of genes involved in lipid biosynthesis in mice 30) . Therefore, nocturnal intermittent hypoxia may increase serum triglyceride levels.…”

“…Being overweight may also be associated with metabolic risk factors indirectly, mediated by nocturnal intermittent hypoxia. For example, reduced oxygen saturation enhances sympathetic activity to raise blood pressure 23) and the production of VLDL in liver, and raises blood triglyceride levels 30) , common pathways in overweight individuals. Therefore, being overweight may weaken the effect of nocturnal intermittent hypoxia on high blood pressure and high triglyceride levels.…”

Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis

“…However, the direct relationship between sleep apnoea or intermittent hypoxia and its cardiovascular consequences is not fully elucidated. We and others have evidence of a role for haemodynamic alterations [5], inflammation [6] and metabolic dysregulations [10,11]. OSA is also frequently associated with obesity, which is the main confounder for detrimental consequences of OSA [12].…”