Hepatocyte ABCA1 deficiency is associated with reduced HDL sphingolipids

Frontiers in Physiology

Physiology

Mingxia Liu¹  Elena Boudyguina¹  John S. Parks²  Thorsten Hornemann³  Alaa Othman³  Heiko Bode³  Arnold von Eckardstein⁴ 

[1] Department of Internal Medicine-Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States;Department of Internal Medicine-Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States;Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, United States;Institute of Clinical Chemistry, University Hospital Zurich and University Zurich, Zurich, Switzerland;Institute of Clinical Chemistry, University Hospital Zurich and University Zurich, Zurich, Switzerland;Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, United States;

关键词: sphingolipids;    Tangier disease;    serine-palmitoyltransferase;    HDL;    LDL;    lipoprotein;   

DOI  :  10.3389/fphys.2023.1208719

 received in 2023-04-19, accepted in 2023-07-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

ATP binding cassette transporter A1 (ABCA1) limits the formation of high density lipoproteins (HDL) as genetic loss of ABCA1 function causes virtual HDL deficiency in patients with Tangier disease. Mice with a hepatocyte-specific ABCA1 knockout (Abca1 HSKO) have 20% of wild type (WT) plasma HDL-cholesterol levels, suggesting a major contribution of hepatic ABCA1 to the HDL phenotype. Whether plasma sphingolipids are reduced in Tangier disease and to what extent hepatic ABCA1 contributes to plasma sphingolipid (SL) levels is unknown. Here, we report a drastic reduction of total SL levels in plasma of a Tangier patient with compound heterozygosity for mutations in ABCA1. Compared to mutation-free controls, heterozygous mutations in ABCA1 had no significant effect on total SLs in plasma; however, apoB-depleted plasma showed a reduction in total SL also in het carriers. Similarly, liver specific Abca1 KO mice (Abca1 HSKO) showed reduced total sphingolipids in plasma and liver. In parallel, apoM and sphingosine-1-phosphate (S1P) levels were reduced in plasma of Abca1 HSKO mice. Primary hepatocytes from Abca1 HSKO mice showed a modest, but significant reduction in total SLs concentration compared to WT hepatocytes, although SL de novo synthesis and secretion were slightly increased in Abca1 HSKO hepatocytes. We conclude that hepatic ABCA1 is a signficant contributor to maintaining total plasma pool of HDL sphingolipids, including sphingomyelins and S1P.

【 授权许可】

Unknown   
Copyright © 2023 Othman, Liu, Bode, Boudyguina, von Eckardstein, Parks and Hornemann.