A role for hepatic scavenger receptor class B, type I in decreasing high density lipoprotein levels in mice that lack phosphatidylethanolamine N-methyltransferase.
Phosphatidylethanolamine N-methyltransferase (PEMT) is a liver-specific enzyme that converts phosphatidylethanolamine to phosphatidylcholine (PC). Mice that lack PEMT have reduced plasma levels of PC and cholesterol in high density lipoproteins (HDL). We have investigated the mechanism responsible for this reduction with experiments designed to distinguish between a decreased formation of HDL particles by hepatocytes or an increased hepatic uptake of HDL lipids. Therefore, we analyzed lipid efflux to apoA-I and HDL lipid uptake using primary cultured hepatocytes isolated from Pemt(+/+) and Pemt(-/-) mice. Hepatic levels of the ATP-binding cassette transporter A1 are not significantly different between Pemt genotypes. Moreover, hepatocytes isolated from Pemt(-/-) mice released cholesterol and PC into the medium as efficiently as did hepatocytes from Pemt(+/+) mice. Immunoblotting of liver homogenates showed a 1.5-fold increase in the amount of the scavenger receptor, class B, type 1 (SR-BI) in Pemt(-/-) compared with Pemt(+/+) livers. In addition, there was a 1.5-fold increase in the SR-BI-interacting protein PDZK1. Lipid uptake experiments using radiolabeled HDL particles revealed a greater uptake of [(3)H]cholesteryl ethers and [(3)H]PC by hepatocytes derived from Pemt(-/-) compared with Pemt(+/+) mice. Furthermore, we observed an increased association of [(3)H]cholesteryl ethers in livers of Pemt(-/-) compared with Pemt(+/+) mice after tail vein injection of [(3)H]HDL. These results strongly suggest that PEMT is involved in the regulation of plasma HDL levels in mice, mainly via HDL lipid uptake by SR-BI.
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Julie C
JC
Robichaud
Gordon A
GA
Francis
Dennis E
DE
Vance
D000818:Animals; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D005260:Female; D022781:Hepatocytes / Q000201:enzymology*; D006706:Homeostasis / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000235:genetics / Q000378:metabolism; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*
D008076:Cholesterol, HDL; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C514896:PDZK1 protein, mouse; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C483858:phosphatidylethanolamine; D050918:Phosphatidylethanolamine N-Methyltransferase