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Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit
Jeffrey L Pitman1, David J Bonnet, Linda K Curtiss
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA.
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.
Insights
A novel mouse mutation, couch potato (cpto), significantly lowers cholesterol by affecting the Mia2 protein, a key player in liver ER-to-Golgi transport. This discovery reveals Mia2
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Cholesterol homeostasis is crucial for health.
- Hepatic (liver) lipoprotein metabolism plays a central role in regulating plasma cholesterol levels.
- Endoplasmic reticulum (ER)-to-Golgi trafficking is essential for protein secretion and processing.
Purpose of the Study:
- To identify novel genetic factors influencing plasma cholesterol levels.
- To characterize the molecular function of the Mia2 protein in hepatic lipid metabolism.
- To investigate the role of Mia2 in ER-to-Golgi protein transport.
Main Methods:
- Forward genetic screening in mice to identify mutations affecting plasma cholesterol.
- Molecular characterization of the identified mutation and its effect on the Mia2 protein.
- Biochemical and cellular localization studies of Mia2.
- Analysis of lipoprotein profiles in mutant and wild-type mice.
Main Results:
- A recessive mutation, couch potato (cpto), was identified that dramatically reduces plasma cholesterol across all lipoprotein classes (VLDL, LDL, HDL).
- The cpto mutation affects a conserved residue in the Src homology domain 3 (SH3) of the Mia2 protein.
- Mia2 is a hepatic protein localized to ER exit sites and interacts with COPII proteins (Sec23 and Sec24), indicating a role in ER-to-Golgi transport.
- Mia2(cpto/cpto) mice exhibit significantly lower circulating VLDL, LDL, HDL, and triglycerides.
Conclusions:
- Mia2 is a novel hepatic protein involved in ER-to-Golgi trafficking.
- Mia2 plays a critical role in regulating cholesterol and triglyceride metabolism.
- The cpto mutation provides a valuable tool for studying hepatic lipid transport and cholesterol regulation.
