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1 Medicine, Johns Hopkins University, Baltimore, MD, USA
2 Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA
3 Medicine, University of Maryland, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: vpolots1{at}jhmi.edu.
We have previously shown that exposure of C57BL/6J mice to intermittent hypoxia (IH) leads to: (1) hypertriglyceridemia due to up-regulation of pathways of lipid biosynthesis, including sterol regulatory element binding protein 1 (SREBP-1) and stearoyl CoA desaturase 1 (SCD-1); and (2) hypercholesterolemia due to impaired cholesterol uptake. The goal of the present study was to examine whether HIF-1 is implicated in changes in lipid metabolism induced by IH. Lean Hif1a+/- mice, which are heterozygous for a null allele at the locus encoding the HIF-1
subunit, and their wild-type Hif1a+/+ littermates (WT) were exposed to IH or control conditions for 5 days. IH increased fasting blood glucose, serum total- and HDL-cholesterol, phospholipids, triglycerides (TG), and leptin in mice of both genotypes, whereas serum insulin and interleukin-6 were elevated only in WT mice. The impact of IH on serum TG levels in WT mice was significantly greater than in Hif1a+/- mice (95±9 mg/dl vs 66±6 mg/dl, p < 0.05), whereas cholesterol and glucose levels were affected independently of genotype. Under hypoxic conditions, mRNA and protein levels of SREBP cleavage activating protein (SCAP) and SCD-1, and protein levels of nuclear isoform of SREBP-1 in the liver were induced to significantly higher levels in WT mice than in Hif1a+/- mice. We conclude that (1) the effect of IH on serum TG levels is mediated through HIF-1; (2) HIF-1 may impact on post-transcriptional regulation of SREBP-1; and (3) the effect of IH on serum cholesterol levels was not altered by partial HIF-1 deficiency.
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