PMID- 16639077
OWN - NLM
STAT- MEDLINE
DCOM- 20060928
LR  - 20210217
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 47
IP  - 7
DP  - 2006 Jul
TI  - The role of lipolysis in mediating the proinflammatory effects of very low 
      density lipoproteins in mouse peritoneal macrophages.
PG  - 1406-15
AB  - Hypertriglyceridemia is an important risk factor for atherosclerosis, especially 
      in obesity. Macrophages are one of the primary cell types involved in 
      atherogenesis and are thought to contribute to lesion formation through both 
      lipid accumulation and proinflammatory gene expression. In this study, we sought 
      to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid 
      accumulation on macrophage proinflammatory processes. Incubation of mouse 
      peritoneal macrophages with 100 microg/ml VLDL for 6 h led to 2.8- and 3.7-fold 
      increases in intracellular TGs and FFAs, respectively (P < 0.05). The 
      inflammatory proteins tumor necrosis factor-alpha, interleukin-1beta, monocyte 
      chemoattractant protein-1, intercellular adhesion molecule-1, matrix 
      metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1alpha 
      (MIP-1alpha) were all upregulated by at least 2-fold (P < 0.05) in a 
      dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory 
      gene expression coincided with the phosphorylation of the mitogen-activated 
      protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 
      1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and 
      was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG 
      hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of 
      intracellular TG and FFA accumulation and was accompanied by the amelioration of 
      ERK1/2 phosphorylation and MIP-1alpha gene expression. These data indicate that 
      VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, 
      plays a substantive role in mediating the proinflammatory effects of VLDL. These 
      data have important implications for the direct proatherogenic effects of VLDL on 
      macrophage-driven atherosclerosis.
FAU - Saraswathi, Viswanathan
AU  - Saraswathi V
AD  - Department of Molecular Physiology and Biophysics,Vanderbilt University Medical 
      Center, Nashville, TN 37232, USA.
FAU - Hasty, Alyssa H
AU  - Hasty AH
LA  - eng
GR  - DK-20593/DK/NIDDK NIH HHS/United States
GR  - DK-26657/DK/NIDDK NIH HHS/United States
GR  - DK-59637/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060425
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (Chemokine CCL3)
RN  - 0 (Chemokine CCL4)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Lipoproteins, VLDL)
RN  - 0 (Macrophage Inflammatory Proteins)
RN  - 0 (Triglycerides)
SB  - IM
MH  - Animals
MH  - Chemokine CCL3
MH  - Chemokine CCL4
MH  - Esterification
MH  - Female
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Hydrolysis
MH  - In Vitro Techniques
MH  - Inflammation Mediators/*metabolism
MH  - Lipid Metabolism
MH  - *Lipolysis/drug effects
MH  - Lipoproteins, VLDL/*metabolism/pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Macrophage Inflammatory Proteins/biosynthesis
MH  - Macrophages, Peritoneal/drug effects/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphorylation
MH  - Triglycerides/metabolism
EDAT- 2006/04/28 09:00
MHDA- 2006/09/29 09:00
CRDT- 2006/04/28 09:00
PHST- 2006/04/28 09:00 [pubmed]
PHST- 2006/09/29 09:00 [medline]
PHST- 2006/04/28 09:00 [entrez]
AID - S0022-2275(20)33184-9 [pii]
AID - 10.1194/jlr.M600159-JLR200 [doi]
PST - ppublish
SO  - J Lipid Res. 2006 Jul;47(7):1406-15. doi: 10.1194/jlr.M600159-JLR200. Epub 2006 
      Apr 25.