Cirrhosis is the tenth leading cause of deaths in the United States in males and the twelfth leading cause of death in females. Non-alcoholic fatty liver disease (NAFLD) may account for the majority of patients who have cryptogenic cirrhosis. The majority of cases of NAFLD are related to metabolic syndrome which includes obesity, type 2 diabetes mellitus, and hypertriglyceridemia. According to retrospective data approximately 3% of the American people have NASH (non-alcoholic steatohepatitis). Our long-term consequence of disease progression to cirrhosis will impose great challenges to the American people. The long-term goal is to elucidate the molecular basis for liver fibrosis, which can ultimately lead to cirrhosis. This proposal meets the mission of the action plan for liver disease research. In the prior funding period, we have convincingly demonstrated that leptin, an adipocytokine produced primarily by white adipose tissue, is a profibrogenic cytokine in the development of hepatic fibrosis. Leptin augments net production of extracellular matrix (ECM) by increasing hepatic stellate cell proliferation (HSC), increases type I collagen synthesis and increases tissue inhibitor of metalloproteinase 1 (TIMP-1);and impedes a timely death of HSCs by strongly inhibiting apoptosis. The overall goal of the current proposal is to demonstrate the biological consequences of leptin and adiponectin as novel modulators of liver fibrosis. We hypothesize that adiponectin is protective against leptin-induced hepatic fibrosis in vitro and in vivo by AMPK blockade of Jak2/Stat3 signal transduction.
Three specific aims have been designed to test this hypothesis. (1). To dissect the molecular pathway whereby adiponectin-activated AMPK impedes Jak2/Stat3 signal transduction, and determine whether leptin enhanced signaling via the PI-3K/Akt and extracellular regulated kinase (Erk, p44/p42), and p38 pathways are directly inhibited as assessed by HSC proliferation and apoptosis.(2).To demonstrate that adiponectin antagonizes leptin's action in the rat HSC by reducing net production of extracellular matrix (ECM) molecules, decreasing the transcriptional activity of tissue inhibitor of metalloproteinase I (TIMP-1) and increasing the functional activity of matrix metalloproteinases (MMPs) that are known to degrade type I collagen. (3). To employ adiponectin knockout (Ad KO) mice to elucidate in vivo how adiponectin modulates the biological effect of leptin in hepatic fibrogenesis as assessed by carbon tetrachloride (CCl4) exposure.

Public Health Relevance

Cirrhosis is a major cause of death in the United States. A primary focus of the laboratory is to unlock molecular switches that regulate the scar tissue known to cause this chronic liver disease. We have observed that two hormones associated with fat metabolism -leptin and adiponectin- can alter the dynamics of scar formation in the liver as well as in the hepatic cells associated with this disease in humans. The project seeks to determine whether adiponectin can act as a protector from the harmful effects of leptin in liver fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062092-07
Application #
7600655
Study Section
Special Emphasis Panel (ZRG1-DIG-C (05))
Program Officer
Doo, Edward
Project Start
2002-07-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
7
Fiscal Year
2009
Total Cost
$329,375
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Kumar, Pradeep; Smith, Tekla; Raeman, Reben et al. (2018) Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells. J Biol Chem 293:12781-12792
Raeman, Reben; Anania, Frank A (2018) Therapy for steatohepatitis: Do macrophages hold the clue? Hepatology 67:1204-1206
Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev et al. (2017) CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. Hepatology 65:661-677
Chopyk, Daniel M; Kumar, Pradeep; Raeman, Reben et al. (2017) Dysregulation of junctional adhesion molecule-A contributes to ethanol-induced barrier disruption in intestinal epithelial cell monolayers. Physiol Rep 5:
Rahman, Khalidur; Desai, Chirayu; Iyer, Smita S et al. (2016) Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol. Gastroenterology 151:733-746.e12
Taba Taba Vakili, Sahar; Kailar, Roshni; Rahman, Khalidur et al. (2016) Glial cell line-derived neurotrophic factor-induced mice liver defatting: A novel strategy to enable transplantation of steatotic livers. Liver Transpl 22:459-67
Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi et al. (2016) Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-? expression. Am J Physiol Gastrointest Liver Physiol 310:G103-16
Rahman, Khalidur; Liu, Yunshan; Kumar, Pradeep et al. (2016) C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis. Lab Invest 96:895-908
Pillai, Anjana A; Anania, Frank A; Pearlman, Brian L (2016) Caution: Reactivation of Hepatitis B during Hepatitis C Treatment with Direct-Acting Antiviral Therapy. Am J Gastroenterol 111:1854-1856
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222

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