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Abstract

OBJECTIVE

Dysregulation of hepatic cholesterol metabolism can contribute to elevated circulating cholesterol levels, which is a significant risk factor for cardiovascular disease. Cholesterol homeostasis in mammalian cells is tightly regulated by an integrated network of transcriptional and post-transcriptional signalling pathways. Whilst prior studies have identified many of the central regulators of these pathways, the extended supporting networks remain to be fully elucidated.

METHODS

Here, we leveraged an integrated discovery platform, combining multi-omics data from 107 strains of mice to investigate these supporting networks. We identified retinol dehydrogenase 11 (RDH11; also known as SCALD) as a novel protein associated with cholesterol metabolism. Prior studies have suggested that RDH11 may be regulated by alterations in cellular cholesterol status, but its specific roles in this pathway are mostly unknown.

RESULTS

Here, we show that mice fed a Western diet (high fat, high cholesterol) exhibited a significant reduction in hepatic Rdh11 mRNA expression. Conversely, mice treated with a statin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitor) exhibited a 2-fold increase in hepatic Rdh11 mRNA expression. Studies in human and mouse hepatocytes demonstrated that RDH11 expression was regulated by altered cellular cholesterol conditions in a manner consistent with SREBP2 target genes HMGCR and LDLR. Modulation of RDH11 in vitro and in vivo demonstrated modulation of pathways associated with cholesterol metabolism, inflammation and cellular stress. Finally, RDH11 silencing in mouse liver was associated with a reduction in hepatic cardiolipin abundance and a concomitant reduction in the abundance of proteins of the mitochondrial electron transport chain.

CONCLUSION

Taken together, these findings suggest that RDH11 likely plays a role in protecting cells against the cellular toxicity that can arise as a by-product of endogenous cellular cholesterol synthesis.

摘要

目的

肝脏胆固醇代谢失调会导致循环胆固醇水平升高，这是心血管疾病的一个重要危险因素。哺乳动物细胞中的胆固醇稳态受到转录和转录后信号通路整合网络的严格调控。虽然先前的研究已经确定了这些通路的许多核心调节因子，但扩展的支持网络仍有待充分阐明。

方法

在这里，我们利用一个整合的发现平台，结合来自107株小鼠的多组学数据来研究这些支持网络。我们将视黄醇脱氢酶11（RDH11；也称为SCALD）鉴定为一种与胆固醇代谢相关的新蛋白。先前的研究表明，RDH11可能受细胞胆固醇状态改变的调节，但其在该通路中的具体作用大多未知。

结果

在这里，我们表明喂食西方饮食（高脂肪、高胆固醇）的小鼠肝脏Rdh11 mRNA表达显著降低。相反，用他汀类药物（3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）抑制剂）治疗的小鼠肝脏Rdh11 mRNA表达增加了2倍。在人和小鼠肝细胞中的研究表明，RDH11的表达受细胞胆固醇条件改变的调节，其方式与SREBP2靶基因HMGCR和LDLR一致。在体外和体内对RDH11的调节表明，与胆固醇代谢、炎症和细胞应激相关的通路受到了调节。最后，小鼠肝脏中RDH11的沉默与肝脏心磷脂丰度的降低以及线粒体电子传递链蛋白丰度的相应降低有关。