United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, MD 20705, USA.
Atherosclerosis. 2012 Jun;222(2):409-16. doi: 10.1016/j.atherosclerosis.2012.03.033. Epub 2012 Apr 11.
Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production.
At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3β mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats.
These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.
肝内极低密度脂蛋白（VLDL）颗粒的过度生成是 2 型糖尿病（T2D）中脂蛋白失调的主要异常。本研究旨在探讨与胰岛素抵抗相关的全身/肝炎症与载脂蛋白（apo）B100 含量的 VLDL 生成之间的关系。
19 周龄时，Otsuka Long-Evans Tokushima Fatty（OLETF）大鼠表现出全身炎症（血浆 TNF-α和白细胞介素（IL）-6 水平升高）、胰岛素抵抗（血浆视黄醇结合蛋白 4 和可溶性 CD36 水平升高）、血脂异常和脂肪肝（血浆和肝脏甘油三酯和胆固醇水平升高，以及总 VLDL、VLDL（1）、VLDL（2）-apoB100 和 VLDL-甘油三酯过度生成），与对照组大鼠相比。在 OLETF 大鼠的肝脏中，tnf、il1b 和 il6 的 mRNA 水平升高，但抗炎蛋白锌指蛋白 36 及其 mRNA 表达减少。我们还发现 OLETF 大鼠的胰岛素受体（InsR）底物（IRS）2 的肝 mRNA、蛋白水平和酪氨酸磷酸化（pY）降低，但 InsR 和 Akt 蛋白的 pY 和磷酸化 Akt（ser437）降低；然而，蛋白酪氨酸磷酸酶-1B 蛋白过度表达。葡萄糖转运蛋白 1 和 2 和糖原合酶的基因表达降低，但磷酸酶和张力蛋白同源物缺失于染色体 10 和糖原合酶激酶 3β mRNA 表达升高，与对照组相比。固醇调节元件结合蛋白-1c mRNA、ATP 结合盒转运蛋白 A1 mRNA、微粒体甘油三酯转移蛋白 mRNA/蛋白和 CD36 mRNA/蛋白水平升高，脂蛋白脂肪酶和 Niemann-Pick c1-like1 mRNA 水平降低，这些都参与了脂生成。OLETF 大鼠的 sirtuins1-3 mRNA 水平也降低。
这些异常基因、蛋白质表达和与炎症、胰岛素信号转导和脂生成相关的多个途径的磷酸化可能是 T2D 中观察到的 VLDL-apoB100 颗粒过度生成的重要潜在因素。我们的数据有助于进一步了解脂蛋白血症与全身代谢紊乱、脂肪肝和肝代谢途径失调之间的关系。
