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Jiang, Xian-Cheng
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Spring 2019
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2019-01-16
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Doctoral Thesis
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Phospholipids are important to form lipoprotein in the plasma and lipid bilayer of plasma membrane. Phospholipids are closely related to lipid metabolism and atherogenesis. In this thesis, we studied two projects, one is focused on the function of phospholipid transfer protein (PLTP) in adipose tissue and its effect on plasma lipoprotein metabolism, the other one is studying the effect of phospholipid remodeling in macrophage inflammation.
In the first project, we prepared adipocyte-specific PLTP KO mice and found that PLTP ablation resulted in a significant reduction of plasma PLTP activity, phospholipids, cholesterol, and apoA-I, mainly on high density lipoprotein (HDL), but has no effect on non-HDL levels, in comparison to controls. To further investigate the mechanisms behind the reduction of apoA-I and HDL lipids in the plasma, we set up an adipose tissue explants culture and measured apoA-I-mediated cholesterol efflux. We found that endogenous or exogenous PLTP significantly increases cholesterol efflux from the explants. We concluded that adipocyte PLTP plays a small but significant role in PLTP activity in the circulation and in plasma HDL production via promoting cholesterol efflux from adipose tissues.
In the second project, we investigated the role of lysophosphatidylcholine acyltransferase 3 (LPCAT3) on macrophage and inflammation. Phosphatidylcholines (PCs) are structural constituents of cell membranes. The activity of LPCAT is required for addition of polyunsaturated fatty acids to the sn-2 position of PCs, which are remodeled after de novo synthesis, and is therefore required to maintain cell membrane structure and function. The order of LPCAT mRNA levels in mouse macrophages is as follows: LPCAT3 > LPCAT1 > LPCAT2 >> LPCAT4. To investigate the role of LPCAT3 in macrophages, we prepared myeloid cell-specific Lpcat3 knockout (KO) mice and found that Lpcat3 deficiency in macrophage significantly reduced certain polyunsaturated phosphatidylcholines in the plasma membrane. Lpcat3 deficiency significantly increased toll like receptor 4 protein and phosphorylated c-Src in membrane lipid rafts, and increased LPS-induced IL-6 and TNFα releasing through activation of MAP kinases and NFκB. Moreover, the ablation of LPCAT3 in macrophages significantly increase of M1 macrophages. However, to our surprise, macrophage deletion of Lpcat3 in low density lipoprotein receptor (Ldl receptor) KO mice did not have a significant impact on atherogenesis. In conclusion, LPCAT3 is one of major LPCATs in macrophages, involved in PC remodeling. LPCAT3 deficiency promotes macrophage inflammatory response, however, such an effect has a marginal influence on the development of atherosclerosis.
Overall, we studied two proteins in phospholipid metabolism. Although some of the outcomes were not expected, we, for the first time, observed the specific function PLTP in adipose tissue and LPCAT3 in macrophage. These results will guide future studies in searching potential targets for the treatment of cardiovascular diseases.
Citation
Jiang, H. (2019) The impact of phospholipid on lipoprotein metabolism and atherosclerosis. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/15869
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Doctoral Thesis