Urokinase plasminogen activator (uPA) stimulates cholesterol biosynthesis in macrophages through activation of SREBP-1 in a PI3-kinase and MEK-dependent manner.
Urokinase plasminogen activator (uPA) is expressed in human atherosclerotic lesions, predominantly in macrophages, and contributes to atherosclerosis progression. Since atherogenesis is characterized by the formation of cholesterol-loaded macrophage foam cells, we questioned whether uPA atherogenicity may involve macrophage cholesterol accumulation, and by what mechanisms. uPA increased cellular cholesterol content by 44% (mainly unesterified cholesterol) in THP-1 macrophages, and this effect was inhibited by statins. This effect was associated with 172% elevated cholesterol biosynthesis, which required the binding of uPA to its receptor. An upregulation of HMGCoA reductase (HMGCR) expression (protein and mRNA) was noted. Since HMGCR expression is controlled by sterol regulatory element-binding proteins (SREBPs), we next analyzed this issue. Indeed, treatment of macrophages with uPA increased SREBP-1 processing, and mature SEREBP-1 content (by 5.7-fold) in the nucleus. These latter effects were mediated by uPA-induced activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK). Finally, uPA was found to activate MAP-kinase through PI3 kinase (PI3K), as PI3K inhibition abrogated both uPA-induced ERK phosphorylation and cholesterol biosynthesis. In conclusion, uPA-induced macrophage cholesterol accumulation is a novel pathway by which uPA may contribute to accelerated atherosclerosis development. These findings provide new insight into the atherogenicity of uPA and may suggest new novel therapeutic means.
Fuhrman
Bianca
B
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa 31096, Israel. Fuhrman@tx.technion.ac.il
Nitzan
Orna
O
Karry
Rachel
R
Volkova
Nina
N
Dumler
Inna
I
Aviram
Michael
M
D050197:Atherosclerosis / Q000503:physiopathology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D019869:Phosphatidylinositol 3-Kinases; D014568:Urokinase-Type Plasminogen Activator