Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease.
Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease.
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DOI：
10.1016/j.metabol.2016.02.014
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Sanyal AJ
中科院分区：
文献类型：
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作者：
Mota M;Banini BA;Cazanave SC;Sanyal AJ
肝细胞暴露于高浓度的脂质和碳水化合物以及随后的肝细胞损伤分别称为脂毒性和葡萄糖毒性。一个共同点是代谢紊乱，特别是在细胞内能量稳态方面，这是由组织中的葡萄糖耐受不良和胰岛素抵抗引起的。在这篇综述中，我们强调了脂质和碳水化合物引起肝细胞损伤和参与脂毒性和糖毒性的机制，包括内质网应激，氧化应激和线粒体损伤。通过上调参与各种途径的蛋白质，包括PKR样ER激酶（PERK）、CCAAT/增强子结合同源蛋白（CHOP）、c-Jun NH 2-末端激酶-1（JNK）、Bcl-2相互作用介体（BIM）、p53上调的凋亡调节因子（p53）和最终的半胱天冬酶，脂毒性状态下的肝细胞最终经历凋亡。某些脂质的保护作用和可能的药物治疗的目标进行了探讨。最后，我们讨论了高果糖和葡萄糖饮食的作用，有助于细胞器损伤和葡萄糖转运机制差，使高血糖症和高脂血症的分流多余的碳水化合物进入脂肪生成。
The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.