Molecular Pharmacology for Diabetes Group, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia.
PLoS One. 2012;7(2):e30816. doi: 10.1371/journal.pone.0030816. Epub 2012 Feb 15.
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been implicated in hepatic steatosis and insulin resistance. The present study investigated their roles in the development of hepatic steatosis and insulin resistance during de novo lipogenesis (DNL) compared to extrahepatic lipid oversupply. Male C57BL/6J mice were fed either a high fructose (HFru) or high fat (HFat) diet to induce DNL or lipid oversupply in/to the liver. Both HFru and HFat feeding increased hepatic triglyceride within 3 days (by 3.5 and 2.4 fold) and the steatosis remained persistent from 1 week onwards (p<0.01 vs Con). Glucose intolerance (iAUC increased by ∼60%) and blunted insulin-stimulated hepatic Akt and GSK3β phosphorylation (∼40-60%) were found in both feeding conditions (p<0.01 vs Con, assessed after 1 week). No impairment of mitochondrial function was found (oxidation capacity, expression of PGC1α, CPT1, respiratory complexes, enzymatic activity of citrate synthase & β-HAD). As expected, DNL was increased (∼60%) in HFru-fed mice and decreased (32%) in HFat-fed mice (all p<0.05). Interestingly, associated with the upregulated lipogenic enzymes (ACC, FAS and SCD1), two (PERK/eIF2α and IRE1/XBP1) of three ER stress pathways were significantly activated in HFru-fed mice. However, no significant ER stress was observed in HFat-fed mice during the development of hepatic steatosis. Our findings indicate that HFru and HFat diets can result in hepatic steatosis and insulin resistance without obvious mitochondrial defects via different lipid metabolic pathways. The fact that ER stress is apparent only with HFru feeding suggests that ER stress is involved in DNL per se rather than resulting from hepatic steatosis or insulin resistance.
线粒体功能障碍和内质网（ER）应激与肝脂肪变性和胰岛素抵抗有关。本研究比较了从头合成（DNL）与肝外脂质过度供应，探讨了它们在肝脂肪变性和胰岛素抵抗发展中的作用。雄性 C57BL/6J 小鼠分别用高果糖（HFru）或高脂肪（HFat）饮食喂养，以诱导 DNL 或脂质在肝脏中过度供应。HFru 和 HFat 喂养均在 3 天内增加肝甘油三酯（增加 3.5 和 2.4 倍），并且脂肪变性从 1 周开始持续存在（与 Con 相比，p<0.01）。在两种喂养条件下均发现葡萄糖耐量受损（iAUC 增加约 60%）和胰岛素刺激的肝 Akt 和 GSK3β磷酸化减弱（约 40-60%）（与 Con 相比，均 p<0.01，在 1 周后评估）。未发现线粒体功能受损（氧化能力、PGC1α、CPT1、呼吸复合物、柠檬酸合酶和β-HAD 的酶活性表达）。如预期的那样，在 HFru 喂养的小鼠中 DNL 增加（约 60%），在 HFat 喂养的小鼠中减少（32%）（均 p<0.05）。有趣的是，与上调的脂肪生成酶（ACC、FAS 和 SCD1）相关的是，三种 ER 应激途径中的两种（PERK/eIF2α 和 IRE1/XBP1）在 HFru 喂养的小鼠中明显被激活。然而，在 HFat 喂养的小鼠中，在肝脂肪变性发展过程中没有观察到明显的 ER 应激。我们的研究结果表明，HFru 和 HFat 饮食可导致肝脂肪变性和胰岛素抵抗，而没有明显的线粒体缺陷，通过不同的脂质代谢途径。只有在 HFru 喂养时才明显出现 ER 应激的事实表明，ER 应激本身涉及 DNL，而不是由肝脂肪变性或胰岛素抵抗引起的。
