The marked increase in cardiovascular disease in patients with type 2 diabetes (T2D) demands an integrated cardiometabolic approach. Using this approach, the PPG team has had a highly interactive and productive collaboration for the last 10 years and plans to move forward to explore common transcriptional and signaling mechanisms in distinct cell types that contribute to cardiometabolic disease. This goal will be achieved through continued synergistic interactions among the 3 projects and Core A. Project 1 (Tabas) will explore how a common upstream CaMKII/MK2 pathway in hepatocytes (HCs) and macrophages (M?s) promotes insulin resistance and plaque progression, respectively?and how the HC pathway amplifies the M? pathway through systemic insulin resistance. The project has a mechanism-based therapeutic/translational component and involves key collaborations with Drs. Tall and Accili. For example, Drs. Tabas & Tall will explore the novel finding that the M? CaMKII/MK2 pathway down- regulates LXR, thereby impairing a key atheroprotective process, efferocytosis. Project 2 (Tall) will explore the role of T39 in HCs, lesional M?s, and adipocytes. In HCs and M?s, T39 alters LXR activation to promote hepatosteatosis and block the suppressive effect of M? LXR on atherosclerosis. Thus, blocking T39 suppresses both atherosclerosis and fatty liver. Drs. Tall & Tabas with study the role of M? LXR in suppressing atherosclerosis in T39-deficient mice (above). In adipocytes T39 suppresses beiging, which may promote insulin resistance and atherosclerosis. The mechanism involves down-regulation of PPAR?1, which will be explored with Dr. Accili. Project 3 (Accili) addresses a key problem in T2D therapeutics, namely, thiazolidinedione (TZD) use is markedly limited by cardiogenic fluid retention and bone loss. Dr. Accili discovered that PPAR?, the target of TZDs, can be deacetylated, which alters it function and response to TZDs. When TZDs are used in insulin-resistant mice expressing deacetylated mutant PPAR? (2KR), the insulin-sensitizing benefits remain but fluid retention and bone loss are prevented. With Drs. Tabas & Tall., Dr. Accili will investigate the relevance of these findings to atherosclerosis and will explore mechanism. For example, Drs. Accili & Tabas found that M?s from 2KR mice have markedly enhanced efferocytosis, which predicts decreased plaque progression. 2KR mice also display adipose beiging, and Drs. Accili & Tall will assess the impact of this on atherogenesis. Core A (Drs. Wang and Wei) will provide essential support and integration for all of the atherosclerosis studies of the PPG and will also provide statistical and bioinformatic support to ensure rigor and reproducibility for all projects. In summary, through synergistic interactions among the PPG PIs, these new studies will reveal important new concepts and therapeutic targets related to the integrated pathophysiology of cardiometabolic disease.
The marked increase in cardiovascular disease in patients with type 2 diabetes (T2D) demands an integrated cardiometabolic approach. This proposal will use this approach to explore common transcriptional and signaling mechanisms in distinct cell types that contribute to cardiometabolic disease. Through synergistic interactions among the PPG PIs, these new studies will revel important new concepts and therapeutic targets related to the integrated pathophysiology of cardiometabolic disease.
|Molusky, Matthew M; Hsieh, Joanne; Lee, Samuel X et al. (2018) Metformin and AMP Kinase Activation Increase Expression of the Sterol Transporters ABCG5/8 (ATP-Binding Cassette Transporter G5/G8) With Potential Antiatherogenic Consequences. Arterioscler Thromb Vasc Biol 38:1493-1503|
|Cai, Bishuang; Kasikara, Canan; Doran, Amanda C et al. (2018) MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci Signal 11:|
|Accili, Domenico (2018) Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67:1701-1709|
|Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44|
|Kraakman, Michael J; Liu, Qiongming; Postigo-Fernandez, Jorge et al. (2018) PPAR? deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects. J Clin Invest 128:2600-2612|
|Ghorpade, Devram S; Ozcan, Lale; Zheng, Ze et al. (2018) Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 555:673-677|
|Fredman, Gabrielle; Tabas, Ira (2017) Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol 187:1211-1221|
|Doran, Amanda C; Ozcan, Lale; Cai, Bishuang et al. (2017) CAMKII? suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest 127:4075-4089|
|Tabas, Ira; Lichtman, Andrew H (2017) Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 47:621-634|
|Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568|
Showing the most recent 10 out of 98 publications