Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses. Atherosclerosis 2015 Oct;242(2):424-32
Date
08/20/2015Pubmed ID
26288136Pubmed Central ID
PMC4712446DOI
10.1016/j.atherosclerosis.2015.08.012Scopus ID
2-s2.0-84939606543 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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.
Author List
Navratil AR, Vozenilek AE, Cardelli JA, Green JM, Thomas MJ, Sorci-Thomas MG, Orr AW, Woolard MDAuthors
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of WisconsinMichael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApolipoproteins E
Apoptosis
Atherosclerosis
Cell Line
Dinoprostone
Flow Cytometry
Foam Cells
Gene Expression Regulation
Humans
Immunoenzyme Techniques
Inflammation
Interleukin-6
Lipids
Lipoproteins, LDL
Macrophages
Male
Mice
Mice, Knockout
Microscopy, Fluorescence
Nuclear Proteins
Phosphatidate Phosphatase
Plaque, Atherosclerotic
Tumor Necrosis Factor-alpha
