Non alcoholic fatty liver disease (NAFLD) is a major health problem in the United States. It is seen in nonobese and obese patients and accompanied by complications of insulin resistance, type 2 diabetes and cardiovascular disease. Exacerbation of the inflammatory response has been shown to be essential for progression of NAFLD into steatosis, cirrhosis and even hepatocellular carcinoma. Immunoregulation and inflammation are controlled by infiltrating myeloid cells and resident macrophages (Kupffer cells), which regulate activation status of T- cells, NKT cells, NK cells and hepatocytes, all of which are critical for the development of NAFLD. However, the mechanisms that link inflammation to development of NAFLD are poorly understood. Therefore, it is important to identify novel factors and pathways that control the intensity and the duration f the inflammatory response in the liver. Screening for novel regulators of inflammation, we identified disabled homolog 2 (Dab2) as being downregulated in pro-inflammatory M1 and upregulated in anti-inflammatory M2 macrophages. Dab2 is a putative mitogen-responsive phosphoprotein, whose expression is downregulated in various forms of cancer, indicating its role as tumor suppressor. We found that Dab2 binds to components of the NF-kappaB signalling pathway and deletion of Dab2 in myeloid cells in mice resulted in protection of the liver against endotoxemia and high fat diet- induced steatosis. We will test the central hypothesis that myeloid Dab2 is essential for the progression of inflammatory hepatic tissue damage and NAFLD. In a multidisciplinary approach, we will use molecular and cell biological, as well as state of the art immunological methods, lipidomics, and conditional knock out mouse models of endotoxin- and diet- induced liver disease.
Specific Aim 1 will test the hypothesis that Dab2 in myeloid-derived cells controls liver inflammation and NAFLD.
Specific Aim 2 will determine the mechanistic basis for Dab2-dependent regulation of inflammation and Specific Aim 3 will examine the hypothesis that Dab2 in myeloid cells is essential for cross talk with NK cells in the liver.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the Western world, affecting about one-quarter of the US population. Since there is no approved treatment for NAFLD, there is an urgent need for the discovery of new targets for intervention. We discovered that disabled homolog 2 (Dab2) controls inflammation in macrophages and testing the role of Dab2 in progression of hepatic tissue damage and NAFLD will permit devising novel strategies to control the inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK096076-01A1
Application #
8505654
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2013-04-10
Project End
2017-03-31
Budget Start
2013-04-10
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$343,650
Indirect Cost
$126,150
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kerur, Nagaraj; Fukuda, Shinichi; Banerjee, Daipayan et al. (2018) cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med 24:50-61
Meher, Akshaya K; Spinosa, Michael; Davis, John P et al. (2018) Novel Role of IL (Interleukin)-1? in Neutrophil Extracellular Trap Formation and Abdominal Aortic Aneurysms. Arterioscler Thromb Vasc Biol 38:843-853
Serbulea, Vlad; Upchurch, Clint M; Ahern, Katelyn W et al. (2018) Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism. Mol Metab 7:23-34
Adamson, Samantha E; Polanowska-Grabowska, Renata; Marqueen, Kathryn et al. (2018) Deficiency of Dab2 (Disabled Homolog 2) in Myeloid Cells Exacerbates Inflammation in Liver and Atherosclerotic Plaques in LDLR (Low-Density Lipoprotein Receptor)-Null Mice-Brief Report. Arterioscler Thromb Vasc Biol 38:1020-1029
Serbulea, Vlad; Upchurch, Clint M; Schappe, Michael S et al. (2018) Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc Natl Acad Sci U S A 115:E6254-E6263
Olmez, Inan; Brenneman, Breanna; Xiao, Aizhen et al. (2017) Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms. Clin Cancer Res 23:6958-6968
Serbulea, Vlad; DeWeese, Dory; Leitinger, Norbert (2017) The effect of oxidized phospholipids on phenotypic polarization and function of macrophages. Free Radic Biol Med 111:156-168
Dyballa-Rukes, Nadine; Jakobs, Philipp; Eckers, Anna et al. (2017) The Anti-Apoptotic Properties of APEX1 in the Endothelium Require the First 20 Amino Acids and Converge on Thioredoxin-1. Antioxid Redox Signal 26:616-629
Adamson, Samantha E; Griffiths, Rachael; Moravec, Radim et al. (2016) Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation. J Clin Invest 126:1311-22
Tosello-Trampont, Annie-Carole; Krueger, Peter; Narayanan, Sowmya et al. (2016) NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63:799-812

Showing the most recent 10 out of 15 publications