Altered hepatic lipid status and apolipoprotein A-I metabolism in mice lacking phospholipid transfer protein.
The effect of PLTP deficiency on hepatic lipid status and apolipoprotein A-I (apoA-I) biosynthesis in PLTP knockout (PLTP-KO) mice was investigated. PLTP-KO mice exhibited a marked reduction in HDL levels, but also increased triglycerides (TG), phospholipids (PL), and cholesterol in very-low-density lipoproteins (VLDL). Both male and female PLTP-KO mice displayed increased hepatic PL and decreased TG, and in the females, increased hepatic cholesterol was also detected. Primary hepatocytes from PLTP-KO mice displayed a different PL molecular species composition to the wild type (WT) controls, with prominent changes being a reduction of long chain fatty acid-containing and an increase of medium chain mono- or di-unsaturated fatty acid containing PL species. Cultured PLTP-KO hepatocytes synthesized and secreted apoA-I in similar quantities as the WT cells. However, the apoA-I secreted by PLTP-KO hepatocytes contained less choline PL, differing also in phosphatidylcholine/sphingomyelin ratio and fatty acyl species composition when compared to apoA-I from WT hepatocytes. Furthermore, the PLTP-KO-derived PL-deficient apoA-I was less stable in the hepatocyte culture medium than that produced by WT cells. These results demonstrate a complex regulatory role of PLTP in serum and liver lipid homeostasis, as well as in the formation of nascent apoA-I-PL complexes from the liver.
Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O. Box 104, FI-00251 Helsinki, Finland.
Sarah
S
Siggins
Igor
I
Bykov
Martin
M
Hermansson
Pentti
P
Somerharju
Kai
K
Lindros
Tatu A
TA
Miettinen
Matti
M
Jauhiainen
Vesa M
VM
Olkkonen
Christian
C
Ehnholm
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D049294:Phospholipid Transfer Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D008074:Lipoproteins; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D014280:Triglycerides; C510091:phospholipid transfer protein, mouse