Using a CRISPR-based screen, researchers have identified a key regulator of LDLR, which reduces cholesterol concentrations and lowers the risk of heart attacks. The regulator, CSDE1, coordinates the decay of LDLR mRNA, and knockdown of Csde1 in mice protected against cholesterol accumulation. Thus, CSDE1 may be a therapeutic target for lowering cholesterol in humans.
The work was led by John Chorba, MD, a chemical biologist at UCSF and a practicing cardiologist at San Francisco General Hospital. His team published the work in Science Translational Medicine in the article, “Cold shock domain-containing protein E1 is a post-transcriptional regulator of the LDL receptor.”
Heart disease is the leading cause of death in the United States, and high blood cholesterol is a major risk factor. LDLR (low-density lipoprotein receptor) removes cholesterol from the bloodstream. Drugs such as statins boost the activity of LDLR and can lower the risk of heart attacks and atherosclerosis, so scientists are pursuing drugs that can grant even stronger anti-cholesterol effects.
“Lowering LDL beyond that achieved by statins improves clinical outcomes without adverse effects,” the researchers wrote. “Although there is a theoretical concentration at which LDL concentrations could get too low, this has yet to be found in large randomized trials. Whether other LDLR regulatory mechanisms could be leveraged to further treat heart disease remains unknown.”
To uncover potential therapeutic targets in heart disease and to advance our understanding of the biology of LDLR, Chorba’s team used a genome-wide CRISPR interference (CRISPRi) screen for factors involved in LDLR regulation.
“[W]e identified 40 specific regulators of the LDLR that were not previously identified by observational human genetic studies,” they wrote. “Among these, we demonstrated that, in HepG2 cells, CSDE1 regulated the LDLR at least as strongly as statins [HMGCR inhibitors] and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.”
CSDE1 coordinates the decay of the mRNA of the LDLR gene, which helps produce LDLR in the liver. Theoretically, targeting CSDE1 to enhance the production of LDLR mRNA would lower cholesterol accumulation and help prevent heart disease.
The researchers found that knocking down the Csde1 gene in mice upregulates hepatic Ldlr mRNA expression and suppressed cholesterol accumulation. They observed no signs of side effects in the mice.
“The magnitude of LDLR up-regulation imparted by CSDE1 knockdown mirrored or exceeded that of HMGCR and PCSK9 in both tissue culture and mouse models, suggesting that a high-fidelity approach targeting CSDE1-mediated LDLR mRNA decay in the clinic could have similar effects,” the researchers wrote. “In addition, our mechanistic data suggest that targeting CSDE1 could be at least additive with the use of statins.”
Further work to characterize CSDE1’s mechanisms, including its potential role in regulating other transcripts, will be important.