{"doi":"10.1016/j.jlr.2021.100080","title":"Liver-specific deletion of Mttp versus Tm6sf2 reveals distinct defects in stepwise VLDL assembly","abstract":"Hepatic VLDL assembly is proposed as a two-step process in which a small primordial lipoprotein particle is formed in the smooth ER by cotranslational lipidation of apolipoprotein B (APOB) by the lipid transfer chaperone microsomal triglyceride transfer protein (MTTP) (1Ginsberg H.N. ApoB SURFs a Ride from the ER to the Golgi.Cell Metab. 2021; 33: 231-233Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). The nascent VLDL particles are progressively lipidated (step 2) through fusion with ER lipid droplets in a process that requires MTTP and other players, including TM6SF2 (1Ginsberg H.N. ApoB SURFs a Ride from the ER to the Golgi.Cell Metab. 2021; 33: 231-233Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Because MTTP is required for both step 1 and step 2, mice with liver-specific deletion of Mttp (Mttp-LKO) develop hepatic steatosis and complete abrogation of VLDL and APOB secretion (2Raabe M. Veniant M.M. Sullivan M.A. Zlot C.H. Bjorkegren J. Nielsen L.B. Wong J.S. Hamilton R.L. Young S.G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.J. Clin. Invest. 1999; 103: 1287-1298Crossref PubMed Scopus (347) Google Scholar). Both germline (3Smagris E. Gilyard S. BasuRay S. Cohen J.C. Hobbs H.H. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins.J. Biol. Chem. 2016; 291: 10659-10676Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar) and liver-specific Tm6sf2 deletor mice (Tm6sf2-LKO, Tm6sf2f/f Albumin CreTg) (4Newberry E.P. Hall Z. Xie Y. Molitor E.A. Bayguinov P.O. Strout G.W. Fitzpatrick J.A.J. Brunt E.M. Griffin J.L. Davidson N.O. Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.Hepatology. 2021; https://doi.org/10.1002/hep.31771Crossref PubMed Scopus (6) Google Scholar) exhibit steatosis and reduced VLDL triglyceride, but no change in APOB secretion (even in an APOB100-only background (4Newberry E.P. Hall Z. Xie Y. Molitor E.A. Bayguinov P.O. Strout G.W. Fitzpatrick J.A.J. Brunt E.M. Griffin J.L. Davidson N.O. Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.Hepatology. 2021; https://doi.org/10.1002/hep.31771Crossref PubMed Scopus (6) Google Scholar)), consistent with secretion of small and underlipidated VLDL particles in Tm6-LKO mice (3Smagris E. Gilyard S. BasuRay S. Cohen J.C. Hobbs H.H. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins.J. Biol. Chem. 2016; 291: 10659-10676Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 4Newberry E.P. Hall Z. Xie Y. Molitor E.A. Bayguinov P.O. Strout G.W. Fitzpatrick J.A.J. Brunt E.M. Griffin J.L. Davidson N.O. Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer.Hepatology. 2021; https://doi.org/10.1002/hep.31771Crossref PubMed Scopus (6) Google Scholar). We used transmission electron microscopy to visualize intracellular and nascent lipoprotein particles in the ER and Golgi of Mttp-LKO, Tm6sf2-LKO, and Flox control mice. Lipoprotein particles, which appear translucent in the absence of imidazole-buffered osmium staining (2Raabe M. Veniant M.M. Sullivan M.A. Zlot C.H. Bjorkegren J. Nielsen L.B. Wong J.S. Hamilton R.L. Young S.G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.J. Clin. Invest. 1999; 103: 1287-1298Crossref PubMed Scopus (347) Google Scholar), were observed in Golgi of control and Tm6sf2-LKO mice (arrowheads, left and middle panels), but none were detected in the ER or Golgi of Mttp-LKO mice, with Golgi stacks appearing either flat or dilated, with no distinct structures inside (right). Nascent VLDL particles in Tm6sf2-LKO Golgi were smaller compared with controls (lower left, n = 6","journal":"Journal of Lipid Research","year":2021,"id":185175,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":580683,"name":"Gregory W. Strout","orcid":"0000-0002-2027-6851","position":1,"is_corresponding":false},{"id":420916,"name":"James A. J. Fitzpatrick","orcid":"0000-0002-7907-3602","position":2,"is_corresponding":false},{"id":267401,"name":"Nicholas O. Davidson","orcid":"0000-0003-3166-2229","position":3,"is_corresponding":false},{"id":372175,"name":"Elizabeth P. Newberry","orcid":"0009-0002-9250-2149","position":0,"is_corresponding":true}],"reference_count":4,"raw_metadata":null,"created_at":"2026-07-18T23:48:34.992499Z","pmid":"33915141","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":[]}