Hepatic fibrosis is thought to be the result of a wound-healing process, marked by transforming growth factor beta (TGF- beta) production and the resulting upregulation of collagen I synthesis by stellate cells. However the relationship between chronic liver injury and fibrogenesis is not well understood. We have made several original observations regarding a possible mechanism linking chronic injury to fibrogenesis in the liver. First, we have directly demonstrated that hepatic stellate cells (HSC) are able to phagocytose apoptotic bodies of hepatocytes in vitro, and second this results in HSC activation and upregulation of TGF-beta1 and type I collagen production. Based on these preliminary data, we propose a CENTRAL HYPOTHESIS that phagocytosis of apoptotic bodies by HSC induces fibrogenesis in the liver.
The SPECIFIC AIMS of this proposal will be answering two key questions generated by this hypothesis: 1. Is phagocytosis of apoptotic bodies by HSC a specific and regulated process? A) Is phagocytosis by HSC a specific receptor-mediated process? B) Is phosphatidylserine eliciting a signaling cascade leading to HSC activation? 2. What are the signaling pathways leading to TGF-beta1 and type 1 collagen upregulation? A) Is engulfment of apoptotic bodies accompanied by activation of NADPH oxidase? B) Is the activation of the MAP-kinase pathway contributing to type I collagen and TGF-beta1 generation? In summary, inhibition of apoptosis, phagocytosis of apoptotic bodies by HSC, or signaling events occurring as a result of the phagocytic process, may prove to be therapeutic strategies to inhibit liver fibrogenesis and delay or even avoid liver transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK069765-01
Application #
6859314
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2005-05-15
Project End
2010-02-28
Budget Start
2005-05-15
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$124,389
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Jiang, Joy X; Chen, Xiangling; Hsu, Daniel K et al. (2012) Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo. Am J Physiol Gastrointest Liver Physiol 302:G439-46
Jiang, Joy X; Venugopal, Senthil; Serizawa, Nobuko et al. (2010) Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo. Gastroenterology 139:1375-84
Medici, Valentina; Ali, Mohamed R; Seo, Suk et al. (2010) Increased soluble leptin receptor levels in morbidly obese patients with insulin resistance and nonalcoholic fatty liver disease. Obesity (Silver Spring) 18:2268-73
Jiang, Joy X; Mikami, Kenichiro; Venugopal, Senthil et al. (2009) Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. J Hepatol 51:139-48
Jiang, Joy X; Mikami, Kenichiro; Shah, Vijay H et al. (2008) Leptin induces phagocytosis of apoptotic bodies by hepatic stellate cells via a Rho guanosine triphosphatase-dependent mechanism. Hepatology 48:1497-505
Zhan, Shan-Shan; Jiang, Joy X; Wu, Jian et al. (2006) Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43:435-43