Excessive alcohol consumption induces the dysregulation of numerous processes in the cells of the liver leading to such abnormalities as steatosis, inflammation, fibrosis, cirrhosis, cancer and eventually organ failure. The cellular process of receptor-mediated-endocytosis (RME) by the hepatocytic asialoglycoprotein receptor (ASGP-R), is particularly susceptible to the effects of ethanol. Ethanol-induced alterations in ASGPR activity have been identified which lead to impaired receptor-mediated clearance of ligands for this receptor. Of particular interest is cellular fibronectin (cFn), one of the natural ligands for the receptor that is produced in elevated amounts during alcohol liver disease (ALD). The increased deposition of this extracellular matrix (ECM) protein in the interstitial space of Disse is implicated in the development of liver fibrosis, the onset of which is characterized by remodeling of the ECM. This remodeling corresponds with alterations in the balanced interaction between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). We have shown that activities for MMP2 and 9 and TIMP 2 are up-regulated in the presence of exogenous cFn. In addition, a membrane-type (MT)-MMP can be selectively induced by cFn and has been implicated in the activation of secreted proteinases. A consequence of increased cFn, in concert with increased MMP production, is the effect it has on various cell types of the liver: hepatocytes (HC), Kupffer cells (KC), and stellate cells (HSC). Thus, in addition to the effect of cFn on MMP and TIMP production we will also examine the effects on the regulation of the secretion of various cytokines as well as their activation in selected cell populations (HC, KC, HSC). Our working hypothesis is that as a consequence of the altered ASGP-R-mediated clearance of cFn following chronic administration of ethanol, a resultant accumulation of cfn is observed. This accumulation of cFn leads to dysregulation of MMP activity leading to the production of pro-fibrogenic factors that promote further liver damage. To test this hypothesis we will use an ad lib model of feeding ethanol to rats. This model has shown liver injury after 8 weeks of feeding.
The specific aims are: [1] Characterize the effect of exogenously added cFn on isolated rat non-parenchymal cells after alcohol administration. [2] Determine the role soluble factors, generated by liver cells stimulated in vitro with excess cFn, have in the progression of fibrosis by examining their effect on other isolated cultures of parenchymal and non-parenchymal cells. Elucidation of the specific mechanisms underlying the fibrotic changes observed during ALD will be important for the development of effective therapies to halt the progression of disease and reduce current widespread morbidity and mortality rates. ? ? ?
| Aziz-Seible, Razia S; Lee, Serene M; Kharbanda, Kusum K et al. (2011) Ethanol feeding potentiates the pro-inflammatory response of Kupffer cells to cellular fibronectin. Alcohol Clin Exp Res 35:717-25 |
| Aziz-Seible, Razia S; Casey, Carol A (2011) Fibronectin: functional character and role in alcoholic liver disease. World J Gastroenterol 17:2482-99 |
| Aziz-Seible, Razia S; McVicker, Benita L; Kharbanda, Kusum K et al. (2011) Cellular fibronectin stimulates hepatocytes to produce factors that promote alcohol-induced liver injury. World J Hepatol 3:45-55 |
