Serine palmitoyltransferase (SPT) deficient mice absorb less cholesterol.
Serine palmitoyltransferase (SPT) is the key enzyme for the biosynthesis of sphingolipids. It has been reported that oral administration of myriocin (an SPT inhibitor) decreases plasma sphingomyelin (SM) and cholesterol levels, and reduces atherosclerosis in apoE knockout (KO) mice. We studied cholesterol absorption in myriocin-treated WT or apoE KO animals and found that, after myriocin treatment, the mice absorbed significantly less cholesterol than controls, with no observable pathological changes in the small intestine. More importantly, we found that heterozygous Sptlc1 (a subunit of SPT) KO mice also absorbed significantly less cholesterol than controls. To understand the mechanism, we measured protein levels of Niemann-Pick C1-like 1 (NPC1L1), ABCG5, and ABCA1, three key factors involved in intestinal cholesterol absorption. We found that NPC1L1 and ABCA1 were decreased, whereas ABCG5 was increased in the SPT deficient small intestine. SM levels on the apical membrane were also measured and they were significantly decreased in SPT deficient mice, compared with controls. In conclusion, SPT deficiency might reduce intestinal cholesterol absorption by altering NPC1L1 and ABCG5 protein levels in the apical membranes of enterocytes through lowering apical membrane SM levels. This may be also true for ABCA1 which locates on basal membrane of enterocytes. Manipulation of SPT activity could thus provide a novel alternative treatment for dyslipidemia.
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, USA.
Zhiqiang
Z
Li
Tae-Sik
TS
Park
Yan
Y
Li
Xiaoyue
X
Pan
Jahangir
J
Iqbal
David
D
Lu
Weiqing
W
Tang
Liqing
L
Yu
Ira J
IJ
Goldberg
M Mahmood
MM
Hussain
Xian-Cheng
XC
Jiang
D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000042:Absorption; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism*; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*; D014118:Toxins, Biological / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
C462600:ABCG5 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D012333:RNA, Messenger; D014118:Toxins, Biological; D014280:Triglycerides; C107040:lysenin; D002784:Cholesterol; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse; C001996:thermozymocidin