Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance.
Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance.
复制标题
与肝脂肪变性和胰岛素抵抗有关的脂肪生成与脂质过量的过多相对于脂质过量的反应不同。
DOI：
10.1371/journal.pone.0030816
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ye JM
中科院分区：
文献类型：
--
作者：
Ren LP;Chan SM;Zeng XY;Laybutt DR;Iseli TJ;Sun RQ;Kraegen EW;Cooney GJ;Turner N;Ye JM
线粒体功能障碍和内质网应激与肝脏脂肪变性和胰岛素抵抗有关。本研究通过与肝外脂肪供应过剩的比较，探讨了它们在新生脂肪生成(DNL)过程中肝脏脂肪变性和胰岛素抵抗的发生中的作用。雄性C57BL/6J小鼠饲喂高果糖(HFru)或高脂(HFat)饲料，以诱导DNL或肝脏内/向肝脏的脂质供应过剩。HFru和HFat在3天内增加了肝脏甘油三酯(分别增加了3.5倍和2.4倍)，脂肪变性在1周后持续(P<；0.01 vs CON)。在两种喂养条件下都发现了葡萄糖耐量(∼增加了60%)和钝化的胰岛素刺激的肝脏Akt和GSK3β磷酸化(∼40-60%)(p<；0.01vs CON，1周后评估)。线粒体功能(氧化能力、前列环素α、CPT1的表达、呼吸复合体、柠檬酸合成酶和β-HAD的活性)均未受到损害。正如预期的那样，高脂饲料喂养的小鼠的DNL增加了(∼60%)，而高脂饲料喂养的小鼠的DNL降低了(32%)。有趣的是，随着脂肪生成酶(Acc、Fas和Scd1)的上调，三条内质网应激途径中的两条(PERK/eIF2α和IRE1/XBP1)在喂食高脂饮食的小鼠中显著激活。然而，在高脂饲料喂养的小鼠发生肝脏脂肪变性期间，没有观察到明显的内质网应激。我们的研究结果表明，HFru和HFat饮食可以通过不同的脂代谢途径导致肝脏脂肪变性和胰岛素抵抗，而没有明显的线粒体缺陷。内质网应激只在高脂饮食时才明显，这一事实表明内质网应激与DNL本身有关，而不是由于肝脏脂肪变性或胰岛素抵抗所致。
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.
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影响因子：
8
作者：
Lee, Ann-Hwee;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
DOI：
10.1046/j.1365-201x.2003.01162.x
发表时间：
2003-08-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
Hegarty, BD;Furler, SM;Kraegen, EW
通讯作者：
Kraegen, EW
影响因子：
15.9
作者：
Denechaud, Pierre-Damien;Bossard, Pascale;Postic, Catherine
通讯作者：
Postic, Catherine
影响因子：
4.1
作者：
Djouadi, F;Riveau, B;Bastin, J
通讯作者：
Bastin, J
影响因子：
56.9
作者：
Dobrosotskaya, IY;Seegmiller, AC;Rawson, RB
通讯作者：
Rawson, RB