Nonalcoholic fatty liver disease (NAFLD) is increasing rapidly among the US population, and has become major health concerns. NAFLD is often associated with elements of the metabolic syndrome, a clinical constellation of obesity, hypertension, insulin resistance, glucose intolerance and hyperlipidemia. The spectrum of NAFLD extends from simple hepatic steatosis through nonalcoholic steatohepatitis (NASH) to cirrhosis. Liver-related morbidity and mortality correlate with the histological severity of NAFLD. Among various factors that contribute to the rising incidence of NAFLD, dietary factors are known to promote obesity and fatty liver disease. Our long-term objectives are to understand the underlying biochemical and molecular mechanisms which dietary factors contribute to NAFLD pathogenesis and to develop strategies that prevent and treat fatty liver disease. Our preliminary studies show that some of the same dietary factors that promote obesity and fatty liver also influence hepatic NKT cells, components of the innate immune system that balance the local production of pro-inflammatory and anti-inflammatory cytokines. Pro-inflammatory cytokines are known to induce insulin resistance and fatty liver disease. Therefore, alterations in NKT cell populations might cause the relative over-production of Th1 cytokines and tissue-specific insulin resistance. This observation suggests a novel mechanism by which dietary components themselves might modulate inflammatory responses that, in turn, regulate insulin resistance and lead to fatty liver. We plan to evaluate the HYPOTHESIS that certain dietary fatty acids alter liver NKT cell populations, thereby influencing the function of the hepatic innate immune system and causing a local, chronic inflammatory state that ultimately leads to local and systemic insulin resistance and fatty liver disease.
Three specific aims will be addressed:
AIM 1 is to determine the dietary basis for alterations in NKT cell populations and firmly establish the causal relation between hepatic NKT cell depletion and steatosis, AIM 2 is to identify the mechanisms of diet-induced NKT cell depletion, and AIM 3 is to identify the mechanisms that NKT cells regulate the pathogenesis of insulin resistance and steatosis. Mice will be fed certain high fat diets to induce obesity and NAFLD. Hepatic lymphocyte population, inflammatory cytokine expressions and liver histology will be evaluated. Confirmation of this hypothesis has potential implications to develop a more accurate animal model of NAFLD and define molecular characteristics (the NIH Action Plan for Liver Disease Research, Chapter 7, Matrix Cell A3). Results from these proposed studies will help to elucidate the pathogenesis of NAFLD, and may have profound therapeutic implications to identify targets for therapy that might be used in rapid- throughput screening systems (the NIH Action Plan for Liver Disease Research, Chapter 7, Matrix Cell B3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075990-04
Application #
8049245
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2008-02-18
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$341,564
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Konerman, Monica A; Price, Jennifer; Torres, Dawn et al. (2014) Randomized, controlled pilot study comparing large-volume paracentesis using wall suction and traditional glass vacuum bottle methods. Therap Adv Gastroenterol 7:184-92
Liang, Shuwen; Webb, Tonya; Li, Zhiping (2014) Probiotic antigens stimulate hepatic natural killer T cells. Immunology 141:203-10
Tang, Zhao-Hui; Liang, Shuwen; Potter, James et al. (2013) Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease. J Immunol 190:1788-96
Miyake, Yasuhiro; Yamamoto, Kazuhide (2013) Role of gut microbiota in liver diseases. Hepatol Res 43:139-46
Hua, Jing; Liang, Shuwen; Ma, Xiong et al. (2011) The interaction between regulatory T cells and NKT cells in the liver: a CD1d bridge links innate and adaptive immunity. PLoS One 6:e27038
Jiang, Xuan; Leong, Derek; Ren, Yong et al. (2011) String-like micellar nanoparticles formed by complexation of PEG-b-PPA and plasmid DNA and their transfection efficiency. Pharm Res 28:1317-27
Xia, Lu; Hua, Jing; Dray, Xavier et al. (2011) Endoscopic visceral fat removal as therapy for obesity and metabolic syndrome: a sham-controlled pilot study (with video). Gastrointest Endosc 74:637-44
Tang, Y; Bian, Z; Zhao, L et al. (2011) Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol 166:281-90
Zhao, Li; Tang, Yanli; You, Zhengrui et al. (2011) Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One 6:e18909
Hua, Jing; Ma, Xiong; Webb, Tonya et al. (2010) Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease. J Lipid Res 51:1696-703

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