Institute of Biomedicine, Pharmacology, University of Helsinki, Finland. pauli.luoma@fi mnet.fi
Ann Med. 2013 Mar;45(2):194-202. doi: 10.3109/07853890.2012.700116. Epub 2012 Aug 28.
Multiple factors including unhealthy living habits influence the life-maintaining functions of the endoplasmic reticulum (ER) and induce ER stress and metabolic abnormalities. The ER responds to the disturbances by activating mechanisms that increase the capacity to eliminate ER stress. This article elucidates the effects of ER activation that eliminates both ER stress and associated cardiovascular, type 2 diabetic (DM2), and other metabolic diseases. ER-activating compounds eliminate ER stress by lowering elevated cholesterol, regress atherosclerosis, decrease cardiovascular mortality, reduce blood glucose and insulin, and, together with the normalization of glucose-insulin homeostasis, remove insulin resistance, pancreatic β-cell failure, and DM2. A deficient cytochrome P450 activity in hepatic ER leads to cholesterol accumulation that induces stress and xanthoma formation, whereas P450-activating therapy up-regulates apolipoprotein AI and LDLR genes, down-regulates apolipoprotein B gene, and produces an antiatherogenic plasma lipoprotein profile. The ER activation reduces the stress also by eliminating hepatic fat and converting saturated fatty acids (FAs) to unsaturated FAs. Cognitive processes require gene expression modification, and preclinical studies indicate that ER-activating therapy improves cognition. Promotion of healthy lifestyle choices and indicated therapies are key factors in the prevention and elimination of ER stress and associated global health problems.
多种因素，包括不健康的生活习惯，影响内质网（ER）的维持生命功能，并导致 ER 应激和代谢异常。ER 通过激活增加消除 ER 应激能力的机制来应对这些干扰。本文阐述了消除 ER 应激和相关心血管疾病、2 型糖尿病（DM2）及其他代谢性疾病的 ER 激活作用。ER 激活化合物通过降低升高的胆固醇来消除 ER 应激，使动脉粥样硬化消退，降低心血管死亡率，降低血糖和胰岛素水平，并通过恢复葡萄糖-胰岛素稳态使胰岛素抵抗、胰岛β细胞衰竭和 DM2 得到消除。肝 ER 中细胞色素 P450 活性不足导致胆固醇积累，从而引起应激和黄瘤形成，而 P450 激活治疗可上调载脂蛋白 AI 和 LDLR 基因，下调载脂蛋白 B 基因，并产生抗动脉粥样硬化的血浆脂蛋白谱。ER 激活还通过消除肝脂肪和将饱和脂肪酸（FAs）转化为不饱和 FAs 来减轻应激。认知过程需要基因表达的修饰，临床前研究表明 ER 激活治疗可改善认知。促进健康的生活方式选择和适当的治疗是预防和消除 ER 应激及相关全球健康问题的关键因素。
