Nonalcoholic fatty liver disease (NAFLD) is associated with obesity. Because the health impact of NAFLD depends on whether or not cirrhosis occurs, our goal has been to clarify the mechanisms for NAFLD progression. In NAFLD, cirrhosis rarely develops unless steatosis progresses to steatohepatitis (NASH), but not all individuals with NASH become cirrhotic. We identified obesity-related defects in hepatic innate immunity that mediates the pathogenesis of NASH. Because a pivotal event in the transition from "simple" NASH to NASH with fibrosis/cirrhosis is hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSC), we developed a unifying hypothesis that might explain inter-individual differences in the susceptibility to MF-HSC accumulation during NASH. We postulate that NAFLD cirrhosis results from fibrogenic repair of hepatic injury, and HYPOTHESIZE that fibrogenic repair involves dysregulated activation of Hedgehog (Hh) signaling that disrupts normal repair-related immune responses. Our hypothesis is based on the following evidence: hepatocyte apoptosis is a key factor that distinguishes NASH from steatosis;hepatocyte death reproducibly triggers regenerative mechanisms;regeneration of chronic fatty liver damage requires expansion/differentiation of progenitors;and the latter processes are regulated by Hedgehog (Hh) ligands produced by cells that accumulate in injured livers, including MF-HSC, immature ductular cells, and NKT cells. Preliminary data suggest Hh-regulated, repair-related mechanisms promote re-accumulation of hepatic NKT cells, switching of hepatic cytokine production from a Th1-predominant to a Th2-predominant profile, and expansion of MF-HSC populations. This is probably important for NAFLD progression because NKT cell accumulation, Th2 polarization of hepatic cytokines, and MF-HSC growth promote fibrosis in other chronic liver diseases. Moreover, inherited (and acquired) differences in two systems that are known to regulate adiposity (i.e., leptin and Hedgehog) may contribute to inter-individual differences in the susceptibility to hepatic fibrosis. During the next funding period, we will determine the significance of Hh-regulated immune mechanisms that influence liver fibrosis, and evaluate if leptin and Hh signaling pathways interact to regulate fibrotic responses to liver injury. The results may expedite development of novel diagnostic tests and treatments for diverse types of obesity-related pathology, including NAFLD.

Public Health Relevance

The results may expedite development of novel diagnostic tests and treatments for diverse types of obesity- related pathology, including NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053792-11
Application #
8272699
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
1999-09-30
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
11
Fiscal Year
2012
Total Cost
$320,463
Indirect Cost
$115,038
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Guy, Cynthia D; Suzuki, Ayako; Abdelmalek, Manal F et al. (2015) Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology 61:98-107
Guy, Cynthia; Suzuki, Ayako; Abdelmalek, Manal et al. (2015) Reply: To PMID 24849310. Hepatology 61:1770-1
Seth, Ratanesh Kumar; Das, Suvarthi; Kumar, Ashutosh et al. (2014) CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8+ T cells aid progression of environment-linked nonalcoholic steatohepatitis. Toxicol Appl Pharmacol 274:42-54
Pereira, Thiago A; Xie, Guanhua; Choi, Steve S et al. (2013) Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int 33:149-61
Seth, Ratanesh Kumar; Kumar, Ashutosh; Das, Suvarthi et al. (2013) Environmental toxin-linked nonalcoholic steatohepatitis and hepatic metabolic reprogramming in obese mice. Toxicol Sci 134:291-303
Swiderska-Syn, Marzena; Suzuki, Ayako; Guy, Cynthia D et al. (2013) Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology 57:1814-25
Xie, Guanhua; Karaca, Gamze; Swiderska-Syn, Marzena et al. (2013) Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58:1801-13
Machado, Mariana Verdelho; Yang, Yiping; Diehl, Anna Mae (2013) The benefits of restraint: a pivotal role for IL-13 in hepatic glucose homeostasis. J Clin Invest 123:115-7
Guy, Cynthia D; Suzuki, Ayako; Zdanowicz, Marzena et al. (2012) Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55:1711-21
Syn, Wing-Kin; Choi, Steve S; Liaskou, Evaggelia et al. (2011) Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53:106-15

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