The central hypothesis to be examined in this R21 proposal is that the class B scavenger receptor, CD36, plays an important role in hepatic stellate cell activation and hepatic fibrogenesis through the alcohol-induced generation of lipid peroxidation products and activation of the nuclear transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-G). The major difficulty in devising specific therapies for alcoholic liver disease has been our limited understanding concerning the mechanisms underlying the progressive nature of the liver injury and fibrosis in this disease process. The class B scavenger receptor CD36 binds oxidized LDL (OxLDL) and is critical in macrophage foam cell formation and lipid flux. Oxidized cholesterol esters and lipid peroxidation products have been shown to act as ligands for PPAR-G in cells. The expression of CD36, which takes up oxidized cholesterol esters from OxLDL, is positively regulated by PPAR-G, thereby establishing a positive feedback control loop through which oxidized LDL induces greater CD36 expression which in turn leads to increased OxLDL accumulation in cells. The CD36-thrombospondin complex is required on the cell surface for the formation of activated transforming growth factor-beta (TGF-b). We present preliminary data that PPAR-G agonists similarly increases CD36 expression and function in hepatic stellate cells, linking alcohol-induced generation of lipid peroxidation products and hepatic fibrosis. It is well documented in experimental models of alcoholic liver disease that addition of polyunsaturated fatty acids to the diet enhances liver injury and fibrosis. It is our working hypothesis that the CD36 scavenger receptor is upregulated in alcoholic liver disease and is critical for stellate cell activation and fibrogenesis. We therefore propose basic studies in vitro and in animal models of liver fibrosis that address the specific role of CD36 class B scavenger receptors in hepatic stellate cell activation. We believe the proposed research is likely to generate data that will lead to a regular research project grant.
The specific aims of this R21 Experimental/Developmental Proposal are:
Aim 1 : To determine the extent to which PPARG activation and CD36 expression regulate stellate cell activation. Stellate cell activation will be measured by Collagen expression and secretion of activated TGF-B.
Aim 2 : To document that stellate cells from spontaneously hypertensive rats deficient in CD36 are resistant to activation and fibrogenesis. Moreover, we will determine whether the over expression of CD36 in these CD36-deficient stellate using an adenoviral vector will reconstitute their ability to become activated in response to lipid peroxidation products.
Aim 3 : To determine the influence of hepatic stellate cell CD36 expression on the development of hepatic fibrosis in rodent models. We will determine whether spontaneously hypertensive rats and CD36-deficient mice are resistant to the development of hepatic fibrosis.
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