ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma
J Lipid Res.
Iqbal J1,2, Walsh MT1, Hammad SM3, Cuchel M4, Rader DJ4, Hussain MM5,6,7.
1 Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY.
2 King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Eastern Region, Ministry of National Guard Health Affairs, Al Ahsa, Saudi Arabia.
3 Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC.
4 Institute for Translational Medicine and Therapeutics, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA.
5 Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY firstname.lastname@example.org.
6 Diabetes and Obesity Research Center, New York University Winthrop Hospital, Mineola, NY.
7 Department of Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY.
Year of Publication:
Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (-69%) and SM (-40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (-79%) and SM (-85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.