HMG-CoA Reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing non-sterol isoprenoids, such as dolichol, ubiquinone, farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on non-sterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the non-sterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr null hepatocytes showed endoplasmic reticulum (ER) stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted Dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver, and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

中文翻译：

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HMG-CoA 还原酶急性肝脏特异性缺失后必需类异戊二烯的消耗和 ER 应激诱导。


HMG-CoA 还原酶 (Hmgcr) 是甲羟戊酸途径中的限速酶，被他汀类药物抑制。除了胆固醇之外，Hmgcr 活性也是合成非甾醇异戊二烯类化合物所必需的，例如多醇、泛醌、法尼基化和香叶基香叶基化蛋白质。在这里，我们研究了 Hmgcr 抑制对肝脏中非甾醇类异戊二烯的影响。我们已经建立了新的遗传模型，利用 AAV 介导的 Cre 重组酶 (AAV-Cre) 或 CRISPR/Cas9 (AAV-CRISPR) 的传递，急性删除肝脏甲羟戊酸途径中的基因。 AAV-Cre 对 Hmgcr 的基因删除导致广泛的肝细胞凋亡和代偿性肝再生。在生化水平上，我们观察到甾醇水平降低，非甾醇类异戊二烯、多醇和泛醌消耗。在细胞水平上，Hmgcr 无效肝细胞表现出内质网 (ER) 应激和 N-糖基化受损。我们进一步假设，N-糖基化所必需的多萜醇的消耗可能是导致内质网应激的原因。使用 AAV-CRISPR，我们体细胞破坏了脱氢多羟基化合物二磷酸合酶亚基 (Dhdds)，该亚基编码多羟基化合物生物合成所需的分支点酶。 Dhdds 无效肝脏表现出 ER 应激和 N-糖基化受损，以及细胞凋亡和再生。最后，Hmgcr 和 Dhdds 的联合缺失协同加剧了肝细胞 ER 应激。我们的数据显示了甲羟戊酸衍生的多羟基化合物在肝脏中的关键作用，并表明多羟基化合物的消耗至少部分地导致了有效的 Hmgcr 抑制后的 ER 应激和细胞凋亡。