{"doi":"10.7554/elife.82269","title":"Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol","abstract":"PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice ( Surf4 fl/fl Alb-Cre + ) to investigate the physiologic role of SURF4 in vivo. Surf4 fl/fl Alb-Cre + mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4 fl/fl Alb-Cre + mice, with a corresponding ~50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B (APOB). Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4 fl/fl Alb-Cre + mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.","journal":"eLife","year":2022,"id":249074,"datarank":0.9011117584182968,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.39093215116897345,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.39093215116897345,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":21,"citers_with_citation_signal":17,"citers_with_endowment":17,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE214393"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":889152,"name":"Joseph McCormick","orcid":"0000-0002-4687-4235","position":1,"is_corresponding":false},{"id":889809,"name":"Bolin Xu","orcid":null,"position":2,"is_corresponding":false},{"id":889153,"name":"Yawei Wang","orcid":"0000-0002-2692-7029","position":3,"is_corresponding":false},{"id":889154,"name":"Huan Fang","orcid":"0000-0003-0317-5394","position":4,"is_corresponding":false},{"id":889155,"name":"Xiao Wang","orcid":"0000-0002-4251-9412","position":5,"is_corresponding":false},{"id":718788,"name":"David Siemieniak","orcid":null,"position":6,"is_corresponding":false},{"id":499041,"name":"Rami Khoriaty","orcid":"0000-0003-2539-5953","position":7,"is_corresponding":false},{"id":499038,"name":"Brian T. Emmer","orcid":"0000-0001-7365-1021","position":8,"is_corresponding":false},{"id":889156,"name":"Xiaowei Chen","orcid":"0000-0003-4564-5120","position":9,"is_corresponding":false},{"id":345469,"name":"David Ginsburg","orcid":"0000-0002-6436-8942","position":10,"is_corresponding":false},{"id":499039,"name":"Vi T. Tang","orcid":"0000-0001-6079-9756","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T00:24:19.356023Z","pmid":"36193893","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}