Microsomal Triglyceride Transfer Protein Transfers and Determines Plasma Concentrations of Ceramide and Sphingomyelin but Not Glycosylceramide.
Sphingolipids, a large family of bioactive lipids, are implicated in stress responses, differentiation, proliferation, apoptosis, and other physiological processes. Aberrant plasma levels of sphingolipids contribute to metabolic disease, atherosclerosis, and insulin resistance. They are fairly evenly distributed in high density and apoB-containing lipoproteins (B-lps). Mechanisms involved in the transport of sphingolipids to the plasma are unknown. Here, we investigated the role of microsomal triglyceride transfer protein (MTP), required for B-lp assembly and secretion, in sphingolipid transport to the plasma. Abetalipoproteinemia patients with deleterious mutations in MTP and absence of B-lps had significantly lower plasma ceramide and sphingomyelin but normal hexosylceramide, lactosylceramide, and different sphingosines compared with unaffected controls. Furthermore, similar differential effects on plasma sphingolipids were seen in liver- and intestine-specific MTP knock-out (L,I-Mttp(-/-)) mice, suggesting that MTP specifically plays a role in the regulation of plasma ceramide and sphingomyelin. We hypothesized that MTP deficiency may affect either their synthesis or secretion. MTP deficiency had no effect on ceramide and sphingomyelin synthesis but reduced secretion from primary hepatocytes and hepatoma cells. Therefore, MTP is involved in ceramide and sphingomyelin secretion but not in their synthesis. We also found that MTP transferred these lipids between vesicles in vitro. Therefore, we propose that MTP might regulate plasma ceramide and sphingomyelin levels by transferring these lipids to B-lps in the liver and intestine and facilitating their secretion.
From the Departments of Cell Biology and.
Jahangir
J
Iqbal
From the Departments of Cell Biology and.
Meghan T
MT
Walsh
the Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425.
Samar M
SM
Hammad
the Institute for Translational Medicine and Therapeutics, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Marina
M
Cuchel
the Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy.
Patrizia
P
Tarugi
the Blackburn Cardiovascular Genetics Laboratory, The Robarts Research Institute, London, Ontario N6A 5B7, Canada.
Robert A
RA
Hegele
the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Nicholas O
NO
Davidson
the Institute for Translational Medicine and Therapeutics, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Daniel J
DJ
Rader
the Department of Medicine, Division of Endocrinology, Metabolism, and Medical Genetics, Medical University of South Carolina, Charleston, South Carolina 29425, the Research Service, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29401, and.
Richard L
RL
Klein
From the Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203, the Department of Veterans Affairs New York Harbor Healthcare System, Brooklyn, New York 11209 mahmood.hussain@downstate.edu.
M Mahmood
MM
Hussain
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002518:Ceramides / Q000097:blood*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013109:Sphingomyelins / Q000097:blood*
D002352:Carrier Proteins; D002518:Ceramides; D013109:Sphingomyelins; C106092:microsomal triglyceride transfer protein
apolipoprotein; ceramide; dyslipidemia; lipoprotein; sphingolipid; sphingomyelin