Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses.
Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries and the underlying cause of cardiovascular disease, a major cause of mortality worldwide. The over-accumulation of modified cholesterol-containing low-density lipoproteins (e.g. oxLDL) in the artery wall and the subsequent recruitment and activation of macrophages contributes to the development of atherosclerosis. The excessive uptake of modified-LDL by macrophages leads to a lipid-laden "foamy" phenotype and pro-inflammatory cytokine production. Modified-LDLs promote foam cell formation in part by stimulating de novo lipid biosynthesis. However, it is unknown if lipid biosynthesis directly regulates foam cell pro-inflammatory mediator production. Lipin-1, a phosphatidate phosphohydrolase required for the generation of diacylglycerol during glycerolipid synthesis has recently been demonstrated to contribute to bacterial-induced pro-inflammatory responses by macrophages. In this study we present evidence demonstrating the presence of lipin-1 within macrophages in human atherosclerotic plaques. Additionally, reducing lipin-1 levels in macrophages significantly inhibits both modified-LDL-induced foam cell formation in vitro, as observed by smaller/fewer intracellular lipid inclusions, and ablates modified-LDL-elicited production of the pro-atherogenic mediators tumor necrosis factor-α, interleukin-6, and prostaglandin E2. These findings demonstrate a critical role for lipin-1 in the regulation of macrophage inflammatory responses to modified-LDL. These data begin to link the processes of foam cell formation and pro-inflammatory cytokine production within macrophages.
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA. Electronic address: anavra@lsuhsc.edu.
Aaron R
AR
Navratil
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA. Electronic address: avozen@lsuhsc.edu.
Aimee E
AE
Vozenilek
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA. Electronic address: jcarde@lsuhsc.edu.
James A
JA
Cardelli
Department of Pathology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA. Electronic address: jgre11@lsuhsc.edu.
Jonette M
JM
Green
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: mjthomas@mcw.edu.
Michael J
MJ
Thomas
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: msthomas@mcw.edu.
Mary G
MG
Sorci-Thomas
Department of Pathology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA. Electronic address: aorr@lsuhsc.edu.
A Wayne
AW
Orr
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71130, USA. Electronic address: mwoola@lsuhsc.edu.
Matthew D
MD
Woolard
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000473:pathology; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D005434:Flow Cytometry; D005487:Foam Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001057:Apolipoproteins E; C508600:IL6 protein, human; D015850:Interleukin-6; D008055:Lipids; D008077:Lipoproteins, LDL; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; C485999:LPIN1 protein, human; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D015232:Dinoprostone
Atherosclerosis; Foam cell; Inflammation; Lipid droplet; Lipin-1; Macrophage