LAUSR

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current therapies and known causes of familial hypercholesterolemia. We found that cold shock domain–containing protein E1 (CSDE1) enhanced hepatic LDLR messenger RNA (mRNA) decay via its 3′ untranslated region and regulated atherogenic lipoproteins in vivo. Using parallel phenotypic genome-wide CRISPR interference screens in a tissue culture model, we identified 40 specific regulators of the LDLR that were not previously identified by observational human genetic studies. Among these, we demonstrated that, in HepG2 cells, CSDE1 regulated the LDLR at least as strongly as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In addition, we showed that hepatic gene silencing of Csde1 treated diet-induced dyslipidemia in mice to a similar degree as Pcsk9 silencing. These results suggest the therapeutic potential of targeting CSDE1 to manipulate the posttranscriptional regulation of the LDLR mRNA for the prevention of cardiovascular disease. Our approach of modeling a clinically relevant phenotype in a forward genetic screen, followed by mechanistic pharmacologic dissection and in vivo validation, may serve as a generalizable template for the identification of therapeutic targets in other human disease states. Description A genome-wide CRISPRi screen identifies CSDE1 as a regulator of hepatic LDLR mRNA decay, suggesting it as a target for the treatment of heart disease. Controlling CSDE1 to contain cholesterol levels Therapies that up-regulate the hepatic low-density lipoprotein receptor (LDLR) have been shown to reduce cholesterol concentrations and lower the risk of heart attacks. However, further lowering of cholesterol concentrations beyond what statins can achieve may potentially further reduce heart attack risk. Here, Smith and colleagues conducted a genome-wide CRISPR interference screen to identify further factors involved in hepatic LDLR regulation, identifying cold shock domain–containing protein E1 (CSDE1) as a posttranslational regulator of the stability of LDLR mRNA. Knockdown of Csde1 in mice protected the animals from cholesterol accumulation, even on a cholate-rich diet. These findings suggest that CSDE1 may be a therapeutic target to further lower cholesterol in humans.