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Effect of phospholipid transfer protein and apolipoprotein M in sphingosine-1-phosphate and chylomicron metabolism
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Jiang, Xian-Cheng, Geraghty, Patrick, Garcia-Arcos, Itsaso, Huan, Chongmin, Kollmar, Richard, Premsrirut, Prem
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Abstract
Phospholipid transfer protein (PLTP) is a monomeric protein primarily responsible for the
transfer of hydrophobic molecules, including phospholipids, cholesterol, triglycerides from
apolipoprotein B containing particles to high-density lipoprotein (HDL). Shingosine-1-phoshate
is a lipid mediator which acts on five unique receptors expressed in various tissues. Both PLTP
and S1P have been implicated in cardio-related disease. Germline PLTP KO studies reveal
plasma S1P decreases without affected apoM, a major carrier of S1P which is bound to HDL
particles. From this data, we hypothesize that PLTP could be a carrier for S1P in circulation and
that its carrier function is independent of the apoM-S1P axis. We, therefore, developed single
apoM and inducible PLTP KO lines as well as a double PLTP/apoM KO mice model and
compared plasma changes for S1P. Our theory was that if our hypothesis was correct, double
PLTP/apoM KO should decrease plasma S1P more than single KO models suggesting an
additive or synergetic effect. We observed that single apoM KO reduced plasma S1P roughly
50% and single PLTP KO reduced plasma S1P roughly 40%; however, double KO did not reduce
plasma S1P more than 50%. In addition, we found that PLTP KO also reduced plasma HDL,
suggesting that the S1P reduction observed in this inducible KO model was due to HDL
reduction in circulation. Further, we found that KO of albumin, which has long been thought to
be a non-apoM-related S1P carrier, had no effect on S1P levels suggesting that although PLTP
may not be an independent carrier of S1P, neither is albumin.
Our focus on HDL in this set of experiments also lead us to studying apoM more closely. A
previous report detailed that apoM deficiency led to decreased circulating triglyceride (TG)
levels. In the liver, very low-density lipoproteins (VLDL) are produced; however, in the small
intestine chylomicron (CM) are produced. CM production only happens postprandially or after
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fat loading. These two particles are mostly responsible for the circulation of TG and both contain
apolipoprotein B (apoB) – VLDL has apoB-100 and CM has apoB-48 as their main structural
proteins. After confirming the previously observed apoM deficiency phenotype, we measured
small intestinal as well as liver proteins related to the formation and secretion of apoB-containing
particles. Although the liver and the small intestine have a similar set of proteins responsible for
apoB-containing particle secretion, we found that in the small intestine but not the liver of apoM
KO mice, levels of microsomal triglyceride transfer protein (MTP) and Sar1B are decreased.
Both these proteins are necessary components in the formation and secretion. In addition to this,
we found accumulation of lipids confirmed by Oil Red O Staining in small intestinal cells of
apoM KO mice. To confirm this observation, we conducted electron microscopy of the intestinal
cells using apoM KO mice which showed increased ER lipid accumulation as well as increased
cytosolic lipid droplet accumulation as compared to WT mice. We also observed dysfunction in
the transport of vesicles from the ER to the Golgi in apoM KO mice as compared to WT mice.
Coat protein complex II are the group of proteins responsible for this transfer, one of which is
Sar1B. Other proteins in this complex include Sec12, 23, 24, 13, and 31. We measured protein
levels of Sec 12, 23, and 24 and found they were significantly decreased in the small intestine of
apoM KO mice but not in the liver. In addition to this, we measure the mRNA levels of Sar1B
and MTP in both the liver and small intestines of WT and apoM KO mice. There was no
difference between the two tissues in terms of mRNA for these proteins which indicates that the
effect of apoM deficiency is at the protein level. Together, our data suggests a novel role of apoM
in postprandial TG metabolism. Using apoM as a target may give a method to explore the role of
dietary fat intake in lipid metabolism.
Citation
Jones Q. (2025).Effect of phospholipid transfer protein and apolipoprotein M in sphingosine-1-phosphate and chylomicron metabolism [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/16396