Hepatic fibrosis is the result of increased extracellular matrix deposition by activated hepatic stellate cells (HSCs) and a major cause of morbidity and mortality in end stage liver disease. While hepatocyte death and inflammation drive HSC activation and enhance fibrogenesis, spontaneous death of HSC correlates with resolution of fibrosis. We have recently shown that the endocannabinoid anandamide (AEA) is an extremely efficient inducer of cell death in HSCs, but not in hepatocytes, and that AEA blocks HSC proliferation and inhibits proinflammatory signaling. We propose that endocannabinoids regulate hepatic inflammation, injury and fibrogenesis by (i) selectively inducing cell death in HSCs, (ii) by inhibiting the secretion of proinflammatory and profibrogenic mediators and (iii) by modulating the sensitivity of hepatocytes to injury. To investigate this hypothesis, we will define differences in endocannabinoid signaling between primary HSCs and hepatocytes, and explore mechanisms of endocannabinoid-induced cell death in HSCs with a specific focus on the role of ceramide and mitochondrial reactive oxygen species (Aim 1). To determine functions of the endocannabinoid system in hepatic fibrogenesis in vivo, we will investigate the expression of endocannabinoids and their receptors in normal and fibrotic liver. In addition, we will assess the effect of blocking or increasing endocannabinoid signaling on hepatic inflammation, injury and fibrogenesis in cannabinoid receptor 1-, cannabinoid receptor 2- and vanilloid receptor 1-deficient mice after induction of acute and chronic liver injury (Aim 2). Although it is known that AEA-degrading enzyme fatty acid amide hydrolase (FAAH) is highly expressed in the liver, its functions in the regulation of hepatic inflammation, cell death and fibrogenesis are not known. To determine whether endocannabinoid inactivation regulates endocannabinoid levels and responsiveness in the liver, we will analyze expression and function of the endocannabinoid hydrolases FAAH in HSCs and hepatocytes, and assess whether genetic or pharmacological inactivation of these enzymes modulates hepatic injury, inflammation and fibrogenesis (Aim 3). The pursuit of these three aims will allow us to determine whether modulation of endocannabinoid signaling is a feasible approach to reduce hepatic injury and fibrogenesis, and which components of the endocannabinoid system will provide useful targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075830-04
Application #
7816869
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2007-06-11
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$256,172
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Caviglia, Jorge Matias; Schwabe, Robert F (2015) Mouse models of liver cancer. Methods Mol Biol 1267:165-83
Mederacke, Ingmar; Hsu, Christine C; Troeger, Juliane S et al. (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823