Serine/threonine kinases Akt (also known as PKB), are among the most important and versatile protein kinases at the core of human physiology and disease. Akt regulate numerous cellular processes, including cell growth, glucose and lipid metabolism, differentiation, proliferation, and apoptosis. Three highly homologous Akt isoforms, encoded by three separate genes, are expressed in mammals. Combined deletions of the three Akt isoforms in the mouse suggest compensatory and complementary roles of isoforms. However, the three isoforms also have distinct functions, even though the mechanisms of specificity are only starting to emerge. Studies of the role of Akt, and specifically of Akt isofors, in atherogenesis are very limited. It has been recently shown that genetic ablation of Akt1 promotes coronary atherosclerosis via the enhanced expression of proinflammatory genes in the artery wall in a macrophage independent manner. We have recently explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Our studies have demonstrated a specific, macrophage dependent, atheroprotective role for Akt3 in hyperlipidemic ApoE-/- mice. In a step-by-step fashion, we tested various potential mechanisms and demonstrated that the absence of Akt3 transforms macrophage into cell which aggressively accumulates cholesterol esters via two mechanisms: increased lipoprotein uptake via pinocytosis, and parallel increased protein stability of cholesterol esterifying enzyme ACAT1 (also known as SOAT1). Multiple lines of evidence suggested that Akt3 suppresses atherosclerosis by restricting cholesteryl ester accumulation and foam cell formation in macrophages, an early and critical step in atherogenesis. The mechanism is Akt isoform specific, and our preliminary studies suggest that one mechanism for specificity is via differentia subcellular localization of Akt1 (a major isoform in macrophages) and Akt3 in macrophages. The long-term goal of this proposal is to investigate the molecular mechanism of Akt3 regulation of macrophage function. As a specific hypothesis, we propose that Akt3 specifically suppresses transformation of macrophage into lipid accumulating phenotype by inhibiting macrophage pinocytosis and by regulating a particular branch of cholesterol metabolism - cholesterol esterification via direct regulation of ACAT1 protein stability. We will investigate the role of AK3 in atherogenesis in vivo and in vitro with a particular focus on the molecular mechanisms of regulation of Akt3 activity, ACAT1 expression and pinocytosis.
The need to identify novel mechanisms of atherogenesis, as well as search for new therapeutic approaches, is evident from the high rate of cardiovascular events even in patients on current proven therapies. We identified a new molecular signaling pathway that protects from cardiovascular disease by preventing lipid accumulation in cells of the arterial wall. In this project we will investigate the molecular and cellular details of the pathway and the reasons why this pathway can fail in cardiovascular disease. Our studies of this pathway will allow us to identify new approaches to preventing atherosclerosis.
| Yakubenko, Valentin P; Cui, Kui; Ardell, Christopher L et al. (2018) Oxidative modifications of extracellular matrix promote the second wave of inflammation via ?2 integrins. Blood 132:78-88 |
| Gao, Detao; Podrez, Eugene A (2018) Characterization of covalent modifications of HDL apoproteins by endogenous oxidized phospholipids. Free Radic Biol Med 115:57-67 |
| Biswas, Sudipta; Zimman, Alejandro; Gao, Detao et al. (2017) TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia. Circ Res 121:951-962 |
| Ding, Liang; Zhang, Lifang; Biswas, Sudipta et al. (2017) Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling JCI Insight 2: |
| Ding, Liang; Zhang, Lifang; Kim, Michael et al. (2017) Akt3 kinase suppresses pinocytosis of low-density lipoprotein by macrophages via a novel WNK/SGK1/Cdc42 protein pathway. J Biol Chem 292:9283-9293 |
