Diabetes promotes atherosclerosis in humans, greatly increasing the risk of developing cardiovascular disease. Compelling clinical data show that improving glycemic control early in life has long-term beneficial effects on cardiovascular events in human subjects with type 1 diabetes. Macrophages are likely to play a key role in the stimulatory effects of diabetes on atherosclerosis. Our preliminary studies demonstrate that in addition to stimulating a pro-inflammatory response, diabetes and elevated glucose levels lead to an increased expression of an enzyme that esterifies fatty acids (long-chain acyl-CoA synthetase 1;ACSL1) in macrophages, suggesting a close connection between the inflammatory capacity and ACSL1 in macrophages, diabetes and states of hyperglycemia. Strikingly, the stimulatory effects of diabetes on atherosclerotic lesion formation can be completely prevented by deleting ACSL1 in myeloid cells. No such effect is seen in non-diabetic mice, suggesting that the discovered mechanism is selective for diabetes. The protective effect of ACSL1-deficiency correlates with a reduced release of pro-inflammatory mediators from macrophages. The overall hypothesis of this project is that diabetes promotes atherosclerosis largely through increased glucose uptake in macrophages, which promotes an inflammatory macrophage phenotype that requires ACSL1. Our goal for the proposed project is to address two questions: 1). Does increased glucose uptake in macrophages enhance their pro-inflammatory capacity and atherosclerosis through a mechanism that requires ACSL1?;2). What is the ACSL1-dependent mechanism of glucose-mediated macrophage activation?
These studies will increase our understanding of the molecular and cellular mechanisms involved in diabetes- accelerated atherosclerosis and cardiovascular disease. Identification of such mechanisms might help develop treatment strategies to target cardiovascular complications, and other complications, associated with diabetes.
|Rune, Ida; Rolin, Bidda; Lykkesfeldt, Jens et al. (2018) Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics. Sci Rep 8:5416|
|Bornfeldt, Karin E; Kramer, Farah; Batorsky, Anna et al. (2018) A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis. Am J Pathol 188:343-352|
|Wall, Valerie Z; Barnhart, Shelley; Kramer, Farah et al. (2017) Inflammatory stimuli induce acyl-CoA thioesterase 7 and remodeling of phospholipids containing unsaturated long (?C20)-acyl chains in macrophages. J Lipid Res 58:1174-1185|
|Kothari, Vishal; Bornfeldt, Karin E (2017) Liver Kinase B1 Links Macrophage Metabolism Sensing and Atherosclerosis. Circ Res 121:1024-1026|
|Shimizu-Albergine, Masami; Van Yserloo, Brian; Golkowski, Martin G et al. (2016) SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP. Proc Natl Acad Sci U S A 113:E5685-93|
|Tabas, Ira; Bornfeldt, Karin E (2016) Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res 118:653-67|
|Libby, Peter; Bornfeldt, Karin E; Tall, Alan R (2016) Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res 118:531-4|
|Kanter, Jenny E; Bornfeldt, Karin E (2016) Impact of Diabetes Mellitus. Arterioscler Thromb Vasc Biol 36:1049-53|
|Bornfeldt, Karin E (2016) Does Elevated Glucose Promote Atherosclerosis? Pros and Cons. Circ Res 119:190-3|
|Rune, Ida; Rolin, Bidda; Larsen, Christian et al. (2016) Modulating the Gut Microbiota Improves Glucose Tolerance, Lipoprotein Profile and Atherosclerotic Plaque Development in ApoE-Deficient Mice. PLoS One 11:e0146439|
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