Li Jianguo, Bosch-Marce Marta, Nanayakkara Ashika, Savransky Vladimir, Fried Susan K, Semenza Gregg L, Polotsky Vsevolod Y
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Physiol Genomics. 2006 May 16;25(3):450-7. doi: 10.1152/physiolgenomics.00293.2005. Epub 2006 Feb 28.
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-1alpha (Hif1a)(+/-) mice, which are heterozygous for a null allele at the locus encoding the HIF-1alpha 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-1alpha deficiency.
我们之前已经表明，将C57BL/6J小鼠暴露于间歇性低氧（IH）会导致：1）由于脂质生物合成途径上调，包括固醇调节元件结合蛋白（SREBP）-1和硬脂酰辅酶A去饱和酶（SCD）-1，从而引发高甘油三酯血症；以及2）由于胆固醇摄取受损导致高胆固醇血症。本研究的目的是检查低氧诱导因子（HIF）-1是否与IH诱导的脂质代谢变化有关。瘦型HIF-1α（Hif1a）（+/-）小鼠，其在编码HIF-1α亚基的基因座上为无效等位基因的杂合子，以及它们的野生型（WT）Hif1a（+/+）同窝小鼠被暴露于IH或对照条件下5天。IH增加了两种基因型小鼠的空腹血糖、血清总胆固醇、高密度脂蛋白胆固醇、磷脂、甘油三酯（TG）和瘦素，而血清胰岛素和白细胞介素-6仅在WT小鼠中升高。IH对WT小鼠血清TG水平的影响显著大于Hif1a（+/-）小鼠（95±9 vs. 66±6 mg/dl，P<0.05），而胆固醇和葡萄糖水平的影响与基因型无关。在低氧条件下，WT小鼠肝脏中SREBP裂解激活蛋白（SCAP）和SCD-1的mRNA和蛋白水平以及SREBP-1核异构体的蛋白水平比Hif1a（+/-）小鼠诱导到显著更高的水平。我们得出结论：1）IH对血清TG水平的影响是通过HIF-1介导的；2）HIF-1可能影响SREBP-1的转录后调控；3）部分HIF-1α缺乏并未改变IH对血清胆固醇水平的影响。
