Our long-term goal is to define the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD) in order to develop treatments for this common obesity-related liver disease, To accomplish this, we've studied ob/lob mice because they develop NAFLD spontaneously, and are naturally obese and insulin resistant (the best clinical predictors for NAFLD in humans), oblob mice have a spontaneous mutation in the ob gene that prevents production of leptin. Thus, leptin deficiency causes NAFLD in this strain, Deficiency of- or resistance to- leptin also causes NAFLD in other animals and in humans, This project is trying to define the mechanisms involved. Our GENERAL HYPOTHESIS is that leptin deficiency alters the function of cells that have competent leptin receptors and changes their production of factors that regulate energy homeostasis and viability in hepatocvtes. Thus, injury to mature hepatocytes (which lack functional leptin receptors) develops as a result of changes that occur in immune cells, neuronal cells and endocrine cells that express functional leptin receptors and are directly regulated by leptin. Our work supports this hypothesis. For example, we showed that leptin deficiency causes Kupffer cell dysfunction and reduces hepatic lymphocyte populations that normally regulate the production of Th-1 (pro-inflammatory, anti-fibrogenic) and Th- 2 (anti-inflammatory, pro-fibrogenic) cytokines in the liver. New preliminary data suggest neuronal factors contribute to this immune dysfunction. Given the general importance of immune mechanisms in the pathogenesis of liver disease, this project witl focus on the role of immunologic factors in the pathogenesis of NAFLD.
AIM #1 is to determine how leptin deficiency alters hepatic lymphocyte populations and to determine if Th-1 polarization of cytokine producing cells results. Hypothesis: leptin deficiency -> altered activities of cytokines and neurotransmitters that regulate the viabiliity and differentiation of liver/ymphocytes -> selective depletion of certain lymphocyte populations -->inhibited Th-2 cytokine production -> Th-1 polarization within the fiver.
AIM #2 is to assess potential consequences of hepatocyte exposure to excessive Th-1 cytokines, Hypothesis: Th-1 cytokines -> altered activity of cytokine-regulated transcription factors -> mitochondrial uncoupling protein-2 induction -> decreased ATP production impaired hepatocyte pro/iferation and increased hepatocyte necrosis.
AIM #3 is to determine the importance of leptin itself for the progression of NAFLD. Hvpothesis: Leptin deficiency -> Th-1/Th-2 cytokine imbalance -> hepatic insulin resistance -> early stages of NAFLD, but cytokine imbalance + decreased sympathetic neurotransmitters -> inhibited progression to cirrhosis. In addition to clarifying the mechanisms for NAFLD pathogenesis, this work will also provide information about general mechanisms that mediate the sevedty of liver injury and fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053792-04A2
Application #
6729486
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Doo, Edward
Project Start
1999-09-30
Project End
2009-03-31
Budget Start
2004-09-01
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$361,900
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Alhasson, Firas; Seth, Ratanesh Kumar; Sarkar, Sutapa et al. (2018) High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol 17:1-15
Machado, Mariana Verdelho; Diehl, Anna Mae (2018) Hedgehog signalling in liver pathophysiology. J Hepatol 68:550-562
Seth, Ratanesh K; Das, Suvarthi; Dattaroy, Diptadip et al. (2017) TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic Biol Med 102:260-273
Machado, M V; Michelotti, G A; Jewell, M L et al. (2016) Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis 7:e2096
Machado, Mariana Verdelho; Diehl, Anna Mae (2016) Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology 150:1769-77
Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L et al. (2016) Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model. Dig Dis Sci 61:137-48
Boursier, Jérôme; Mueller, Olaf; Barret, Matthieu et al. (2016) The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63:764-75
Chandrashekaran, Varun; Das, Suvarthi; Seth, Ratanesh Kumar et al. (2016) Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta 1862:32-45
Dattaroy, Diptadip; Seth, Ratanesh Kumar; Das, Suvarthi et al. (2016) Sparstolonin B attenuates early liver inflammation in experimental NASH by modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation. Am J Physiol Gastrointest Liver Physiol 310:G510-25
Verdelho Machado, Mariana; Diehl, Anna Mae (2016) Role of Hedgehog Signaling Pathway in NASH. Int J Mol Sci 17:

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