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We found that cold shock domain\u2013containing protein E1 (CSDE1) enhanced hepatic\n                    <jats:italic>LDLR<\/jats:italic>\n                    messenger RNA (mRNA) decay via its 3\u2032 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\n                    <jats:italic>Csde1<\/jats:italic>\n                    treated diet-induced dyslipidemia in mice to a similar degree as\n                    <jats:italic>Pcsk9<\/jats:italic>\n                    silencing. These results suggest the therapeutic potential of targeting CSDE1 to manipulate the posttranscriptional regulation of the\n                    <jats:italic>LDLR<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abj8670","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T13:58:20Z","timestamp":1663163900000},"source":"Crossref","is-referenced-by-count":23,"title":["Cold shock domain\u2013containing protein E1 is a posttranscriptional regulator of the LDL receptor"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1638-4219","authenticated-orcid":true,"given":"Geoffrey A.","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, 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