Hepatic high-density lipoprotein secretion regulates the mobilization of cell-surface hepatic lipase.
HDL acts much like heparin to liberate hepatic lipase (HL) from cell surface proteoglycans and stimulate triglyceride clearance. Experiments were undertaken to evaluate the effects of factors that stimulate the secretion of HDL from the liver on the release of HL. Treatment of HepG2 cells with linoleic acid phospholipids (LAPL) (12 muM) promotes a similar increase in the accumulation of both HDL and HL in the cell media. LAPL also induce both apoA-I and HL release from primary human hepatocytes. Dilinoleoylphosphatidylcholine has a greater effect on both apoA-I secretion and HL release than palmitoyllinoleoylphosphatidylcholine. HL released from HepG2 cells is inactive and associated with a large HDL complex containing both apoA-I and apoA-II. Inclusion of the PPARalpha inhibitor, MK-886, or MAPK inhibitor, U0126, completely blocks the LAPL-induced apoA-I and HL accumulation in the media. LAPL-treated cell lysates, however, showed no change in HL protein expression nor HL mRNA. LAPL-induced HL release appears to be a consequence of the displacement ability of newly secreted HDL. Overexpression of pre-pro-apoA-I in HepG2 cells increased HL release, while siRNA inhibition of the apoA-I gene reduced HL in the media. The data show that factors that stimulate HDL secretion in hepatocytes act to also increase the release of HL. This may partly explain why HDL therapeutics often impact plasma triglyceride levels.
Chatterjee
Cynthia
C
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada.
Young
Elizabeth K
EK
Pussegoda
Kusala A
KA
Twomey
Erin E
EE
Pandey
Nihar R
NR
Sparks
Daniel L
DL
D016632:Apolipoprotein A-I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism*; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000037:antagonists & inhibitors; D014280:Triglycerides / Q000378:metabolism
D016632:Apolipoprotein A-I; C504173:LIPC protein, human; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D014280:Triglycerides; D008049:Lipase