Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites

J Lipid Res. 2011 Oct;52(10):1775-86. doi: 10.1194/jlr.M017277. Epub 2011 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • COP-Coated Vesicles / metabolism
  • Cholesterol / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Golgi Apparatus / metabolism
  • Lipoproteins / metabolism
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Solanum tuberosum / genetics
  • Solanum tuberosum / metabolism
  • Triglycerides / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • src Homology Domains

Substances

  • Lipoproteins
  • TANGO protein, mouse
  • Triglycerides
  • Tumor Suppressor Proteins
  • melanoma inhibitory activity protein 2, mouse
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Cholesterol