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Physiol. Genomics 25: 450-457, 2006. First published February 28, 2006; doi:10.1152/physiolgenomics.00293.2005
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Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine
² Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine
³ Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

We have previously shown that exposure of C57BL/6J mice to intermittent hypoxia (IH) leads to 1) hypertriglyceridemia due to upregulation of pathways of lipid biosynthesis, including sterol regulatory element binding protein (SREBP)-1 and stearoyl CoA desaturase (SCD)-1; and 2) hypercholesterolemia due to impaired cholesterol uptake. The goal of the present study was to examine whether hypoxia-inducible factor (HIF)-1 is implicated in changes in lipid metabolism induced by IH. Lean HIF-1 (Hif1a)^+/– mice, which are heterozygous for a null allele at the locus encoding the HIF-1 subunit, and their wild-type (WT) Hif1a^+/+ littermates were exposed to IH or control conditions for 5 days. IH increased fasting blood glucose, serum total cholesterol, and high-density lipoprotein-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 that in Hif1a^+/– mice (95 ± 9 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 posttranscriptional regulation of SREBP-1, and 3) the effect of IH on serum cholesterol levels was not altered by partial HIF-1 deficiency.

lipid biosynthesis; sterol regulatory element biding protein; stearoyl coenzyme A desaturase; triglycerides; liver