Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
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DOI：
10.1038/nature09968
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发表时间：
2011-05-26
期刊：
影响因子：
64.8
通讯作者：
Hotamisligil, Goekhan S.
中科院分区：
文献类型：
--
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
高胆固醇血症是动脉粥样硬化发展的主要危险因素之一。在过去的20年中，随着他汀类药物的到来和发展，高胆固醇血症的治疗取得了相当大的进展。他汀类药物可降低心血管事件的发生率25-40%[1]，尽管这种降低可能被认为是不够的，许多患者可能需要额外的治疗以达到更佳的脂质水平并预防心血管事件。此外，在许多冠状动脉疾病患者中，一般血脂异常，特别是高胆固醇血症仍然诊断不足和治疗不足[2]。关于甘油三酯，贝特类药物仍然是目前治疗高脂血症最有效的药物;然而，尽管定期给予这些药物，但仍有很高比例的患者（主要是V型高脂血症患者）的甘油三酯值仍远高于推荐水平。尽管甘油三酯在动脉粥样硬化发病机制中的作用仍存在争议[3]，但哥本哈根黑尔研究[4]等一些研究表明，空腹甘油三酯水平升高是缺血性心脏病的强风险因素，与其他已知的动脉粥样硬化风险因素无关。不仅胆固醇和甘油三酯是血脂治疗的目标，而且增加高密度脂蛋白胆固醇已成为高脂血症治疗的主要目标之一。大量证据表明，HDL-C水平的轻微改善可能会显著降低CV风险[5，6]。如前所述，HDL-C水平每升高1 mg/dl，男性和女性的冠状动脉疾病风险分别降低2%和3%[5，6]。此外，HDL-C在胆固醇从外周组织转运到肝脏中具有重要作用，此外，还具有潜在的抗炎、抗血栓形成和抗氧化作用[7]。尽管有证据支持抑制胆固醇酯转移蛋白可提高人类HDL-C水平并抑制动物动脉粥样硬化的发展，但最近对CETP抑制剂torcetrapib的研究令人失望[8]。人类中的Torcetrapib治疗导致未知机制的死亡率和发病率风险增加[8]。虽然证实HDL-C升高72.1%，低密度脂蛋白胆固醇降低24.9%，
Hypercholesterolemia is one of the main risk factors in the development of atherosclerosis. During the last 20 years, concurrent with the arrival and development of statins, considerable advances were made in the treatment of hypercholesterolemia. Statins were shown to reduce the incidence of cardiovascular events by 25–40%[1], although this reduction may be considered insufficient and many patients may need additional therapy to reach more optimal lipid levels and prevent cardiovascular events. Furthermore, dyslipidemia in general, and hypercholesterolemia in particular, remain underdiagnosed and undertreated in many patients with coronary artery disease [2]. Regarding triglycerides, fibrates continue to be the most effective drugs today for the treatment of hypertriglyceridemia; however, despite the regular administration of these drugs a high proportion of patients, mainly those with type V hyperlipidemia, continue to have triglyceride values well above recommended levels. Although the role of triglycerides in the pathogenesis of atherosclerosis is still controversial [3], some studies such as the Copenhagen Hale Study [4] showed that elevated fasting triglyceride levels were a strong risk factor for ischemic heart disease, independent of other known risk factors for atherosclerosis. Not only are cholesterol and triglycerides the target of lipid treatment, but increasing high-density lipoproteincholesterol has become one of the main objectives in the treatment of hyperlipidemia. There is considerable evidence that a minor improvement in HDL-C levels may significantly reduce CV risk [5, 6]. As previously reported, an increase of 1 mg/dl in HDL-C levels results in a parallel reduction in coronary artery disease risk by 2% in men and 3% in women [5, 6]. Furthermore, HDL-C has a cardinal role in the transport of cholesterol from peripheral tissues to the liver and, in addition, has potential anti-inflammatory, anti-thrombotic and anti-oxidant effects [7].The search for a drug that is effective in increasing HDL-C levels has been frustrating. Although there is evidence supporting the notion that inhibition of cholesteryl ester transfer protein raises HDL-C levels in humans and inhibits the development of atherosclerosis in animals, a recent study with torcetrapib, an inhibitor of CETP, has been disappointing [8]. Torcetrapib therapy in humans resulted in an increased risk of mortality and morbidity of unknown mechanism [8]. Although an increase of 72.1% in HDL-C and a decrease of 24.9% in low-density lipoprotein-cholesterol were confirmed, there was also an elevated
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影响因子：
64.5
作者：
Cao H;Gerhold K;Mayers JR;Wiest MM;Watkins SM;Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
82.9
作者：
Erbay, Ebru;Babaev, Vladimir R.;Mayers, Jared R.;Makowski, Liza;Charles, Khanichi N.;Snitow, Melinda E.;Fazio, Sergio;Wiest, Michelle M.;Watkins, Steven M.;Linton, MacRae F.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
4.8
作者：
Li, YK;Ge, MT;Tabas, I
通讯作者：
Tabas, I
DOI：
10.1083/jcb.200904060
发表时间：
2009-09-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li G;Mongillo M;Chin KT;Harding H;Ron D;Marks AR;Tabas I
通讯作者：
Tabas I
影响因子：
8.2
作者：
Li, SY;Yang, X;Ren, J
通讯作者：
Ren, J