title: Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites.
abstract: Through forward genetic screening in the mouse, a recessive mutation (couch potato, cpto) has been discovered that dramatically reduces plasma cholesterol levels across all lipoprotein classes. The cpto mutation altered a highly conserved residue in the Src homology domain 3 (SH3) domain of the Mia2 protein. Full-length hepatic Mia2 structurally and functionally resembled the related Mia3 protein. Mia2 localized to endoplasmic reticulum (ER) exit sites, suggesting a role in guiding proteins from the ER to the Golgi. Similarly to the Mia3 protein, Mia2's cytosolic C terminus interacted directly with COPII proteins Sec23 and Sec24, whereas its lumenal SH3 domain may facilitate interactions with secretory cargo. Fractionation of plasma revealed that Mia2(cpto/cpto) mice had lower circulating VLDL, LDL, HDL, and triglycerides. Mia2 is thus a novel, hepatic, ER-to-Golgi trafficking protein that regulates cholesterol metabolism.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Pitman
authors.forename: David J
authors.initials: DJ
authors.lastname: Bonnet
authors.forename: Linda K
authors.initials: LK
authors.lastname: Curtiss
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gekakis
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D022181:COP-Coated Vesicles / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011198:Solanum tuberosum / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D008074:Lipoproteins; C495722:TANGO protein, mouse; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; C569192:melanoma inhibitory activity protein 2, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002784:Cholesterol