Objective

Statins are a group of medications that reduce cholesterol synthesis by inhibiting the activity of HMG-CoA reductase, a key enzyme in the mevalonate pathway. The clinical use of statins to lower excess cholesterol levels has revolutionized the cardiovascular field and increased the survival of millions, but some patients have adverse side effects. A growing body of data suggests that some of the beneficial and adverse effects of statins, including their anti-inflammatory, anti-tumorigenic, and myopathic activities, are cholesterol-independent. However, the underlying mechanisms for these effects of statins are not well defined.

Methods

Because Caenorhabditis elegans (C. elegans) lacks the cholesterol synthesis branch of the mevalonate pathway, this organism is a powerful system to unveil the cholesterol-independent effects of statins. We used genetic and biochemical approaches in C. elegans and cultured macrophage-derived murine cells to study the cellular response to statins.

Results

We found that statins activate a conserved p38-MAPK (p38) cascade and that the protein geranylgeranylation branch of the mevalonate pathway links the effect of statins to the activation of this p38 pathway. We propose that the blockade of geranylgeranylation impairs the function of specific small GTPases we identified as upstream regulators of the p38 pathway. Statin-mediated p38 activation in C. elegans results in the regulation of programs of innate immunity, stress, and metabolism. In agreement with this regulation, knockout of the p38 pathway results in the hypersensitivity of C. elegans to statins. Treating cultured mammalian cells with clinical doses of statins results in the activation of the same p38 pathway, which upregulates the COX-2 protein, a major regulator of innate immunity in mammals.

Conclusions

Statins activate an evolutionarily conserved p38 pathway to regulate metabolism and innate immunity. Our results highlight the cytoprotective role of p38 activation under statin treatment in vivo and propose that this activation underlies many of the critical cholesterol-independent effects of statins.

中文翻译：

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他汀类药物介导的p38-MAPK途径的保守激活保护秀丽隐杆线虫免受他汀类药物的胆固醇非依赖性作用。

目的

他汀类药物是一组药物，通过抑制HMG-CoA还原酶（甲羟戊酸途径中的关键酶）的活性来降低胆固醇的合成。他汀类药物降低胆固醇水平的临床应用已彻底改变了心血管领域，并增加了数百万人的存活率，但有些患者有不良副作用。越来越多的数据表明，他汀类药物的某些有益和不良作用，包括其抗炎，抗致瘤和肌病活性，均与胆固醇无关。但是，对于他汀类药物这些作用的潜在机制尚不清楚。

方法

由于秀丽隐杆线虫（C. elegans）缺乏甲羟戊酸途径的胆固醇合成分支，因此该生物体是揭示他汀类药物非胆固醇依赖性作用的强大系统。我们在秀丽隐杆线虫和培养的巨噬细胞源鼠细胞中使用了遗传和生化方法来研究对他汀类药物的细胞反应。

结果

我们发现他汀类药物可激活保守的p38-MAPK（p38）级联，而甲羟戊酸途径的蛋白geranylgeranylation分支将他汀类药物的作用与该p38途径的激活联系起来。我们建议，对香叶基香叶基的抑制作用会损害我们确定为p38途径上游调节剂的特定小GTP酶的功能。秀丽隐杆线虫中Statin介导的p38激活导致先天免疫，应激和代谢程序的调节。与该法规一致，p38途径的敲除导致秀丽隐杆线虫超敏他汀类药物。用临床剂量的他汀类药物处理培养的哺乳动物细胞会导致相同的p38途径活化，从而上调COX-2蛋白，后者是哺乳动物先天免疫的主要调节剂。

结论

他汀类药物激活进化上保守的p38途径，以调节新陈代谢和先天免疫。我们的结果强调了他汀类药物在体内对p38激活的细胞保护作用，并提出这种激活是他汀类药物许多重要的非胆固醇依赖性作用的基础。