These authors contributed equally to this work.
Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice†
Article first published online: 20 MAR 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 5, pages 1356–1368, May 2012
How to Cite
Khatun, I., Zeissig, S., Iqbal, J., Wang, M., Curiel, D., Shelness, G. S., Blumberg, R. S. and Hussain, M.Mahmood. (2012), Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice. Hepatology, 55: 1356–1368. doi: 10.1002/hep.25504
Potential conflict of interest: Nothing to report.
- Issue published online: 19 APR 2012
- Article first published online: 20 MAR 2012
- Accepted manuscript online: 26 NOV 2011 06:45AM EST
- Manuscript Accepted: 13 NOV 2011
- Manuscript Received: 23 SEP 2011
- NIH. Grant Number: DK-46900 and HL95924
- M.M.H.) and AHA Predoctoral Fellowship. Grant Number: 3230023 (to I.K.)
Microsomal triglyceride transfer protein (MTP), essential for apolipoprotein B (apoB) biosynthesis, evolved as a phospholipid transfer protein and acquired triglyceride transfer activity during a transition from invertebrates to vertebrates. But it is unknown whether MTP directly transfers lipids onto apoB in vivo and, if it does, whether both neutral and polar lipid transfer activities of MTP are critical for lipoprotein assembly. The molecular bases for differences in lipid transfer activities with respect to distinct domains in Drosophila MTP (dMTP) and human MTP (hMTP) are not obvious because both proteins have very similar primary, secondary, and tertiary structures. We used an in vivo approach to delineate physiological significance of these distinct lipid transfer activities by expressing dMTP (transfers phospholipids) and hMTP (transfers phospholipids and triglycerides) orthologs using adenoviruses in liver-specific MTP-deficient (L-MTP−/−) mice that have low plasma and high hepatic lipids. Both orthologs improved plasma lipids but plasma triglycerides were lower in dMTP mice due to lower hepatic triglyceride and apoB production. Hepatosteatosis in L-MTP−/− mice was ameliorated to similar levels by both. Attenuation of hepatosteatosis upon dMTP expression pertained to enhanced β-oxidation with no changes in lipogenesis. Phospholipid transfer activity of MTP promoted biogenesis of both apoB48 and apoB100-containing very low density lipoprotein in addition to a phospholipid-rich apoB48-containing high-density lipoprotein particle. Triglyceride transfer activity augmented the biosynthesis of triglyceride-rich lipoproteins by increasing the formation of these particles in the lumen of the endoplasmic reticulum. Conclusion: Based on these findings, we posit that the selective inhibition of MTP triglyceride transfer activity might reduce hyperlipidemia while protecting liver from excess lipid accumulation. (HEPATOLOGY 2011)