Methods for modulation of cholesterol transport

Abstract

Methods for regulation of lipid and cholesterol uptake are described which are based on regulation of the expression or function of the SR-BI HDL receptor. The examples demonstrate that estrogen dramatically downregulates SR-BI under conditions of tremendous upregulation of the LDL-receptor. The examples also demonstrate the upregulation of SR-BI in rat adrenal membranes and other non-placental steroidogenic tissues from animals treated with estrogen, but not in other non-placental non-steroidogenic tissues, including lung, liver, and skin. Examples further demonstrate the uptake of fluorescently labeled HDL into the liver cells of animal, which does not occur when the animals are treated with estrogen. Examples also demonstrate the in vivo effects of SR-BI expression on HDL metabolism, in mice transiently overexpressing hepatic SR-BI following recombinant adenovirus infection. overexpression of the SR-BI in the hepatic tissue caused a dramatic decrease in cholesterol blood levels. These results demonstrate that modulation of SR-BI levels, either directly or indirectly, can be used to modulate levels of cholesterol in the blood.

We claim:  
     
         1 . A method for screening compounds which alter the transport of lipid, cholesterol, lipoprotein or component thereof mediated by SR-BI or a homolog of SR-BI by administering the compound to an animal and measuring at least one parameter selected from the group consisting of cholesterol levels, production of steroid hormones, bile acids levels, and alterations of the chemical composition of lipids, lipoproteins, cholesterol, steroid hormones, bile acids, and vitamin D.  
     
     
         2 . The method of screening of  claim 1  wherein the compound is administered to animals formed by introducing a nucleotide molecule encoding SR-BI under the control of a regulatory molecule selected from the group consisting of tissue specific promoters and promoters which result in overexpression of SR-BI in a tissue.  
     
     
         3 . The method of  claim 2  wherein the animal is selected from the group consisting of animals which are deficient in ApoE, animals which are deficient in LDL receptor, animals with altered levels lipoprotein lipase, animals with altered levels of hepatic lipases, animals which are deficient in Apo A1 or A2, animals with genetic defects in the expression of LRP, and animals with familial hypercholesterolemia.  
     
     
         4 . A method for altering transport of lipid, cholesterol lipoprotein or component thereof into or out of cells comprising inhibiting expression or activity of SR-BI.  
     
     
         5 . The method of  claim 4  wherein transport of lipid, cholesterol, lipoprotein or component thereof into liver, steroidogenic tissues, epithelial cells in the gastrointestinal tract, bile canniculi, bile ducts, or other body compartments is altered.  
     
     
         6 . The method of  claim 5  wherein transport of lipid, cholesterol, lipoprotein or component thereof into steroidogenic tissues is inhibited or stimulated by administration of a hormone inhibiting or stimulating SR-BI expression.  
     
     
         7 . The method of  claim 6  wherein the hormone has estrogen-like activity.  
     
     
         8 . The method of  claim 5  wherein transport of lipid, cholesterol, lipoprotein or component thereof into the bile ducts is inhibited by administering a compound inhibiting transport of the cholesterol by SR-BI.  
     
     
         9 . The method of  claim 4  wherein transport of lipid, cholesterol, lipoprotein or component thereof is inhibited or stimulated by administering a compound which binds to a regulatory nucleic acid sequence and therefore inhibits or stimulates expression of SR-BI.  
     
     
         10 . The method of  claim 4  wherein transport of lipid, cholesterol, lipoprotein or component thereof is inhibited by administering a compound which binds to the SR-BI and prevents binding of lipid, cholesterol, lipoprotein or component thereof to the receptor.  
     
     
         11 . The method of  claim 4  comprising administering a compound which induces expression of SR-BI to increase transport of lipid, cholesterol, lipoprotein or component thereof.  
     
     
         12 . The method of  claim 11  wherein the compound is a viral vector encoding SR-BI.  
     
     
         13 . The method of  claim 12  wherein the viral vector is an adenoviral vector.  
     
     
         14 . A compound which alters the transport of lipid, cholesterol, lipoprotein or component thereof mediated by SR-BI or a homolog of SR-BI.  
     
     
         15 . A pharmaceutical composition comprising the compound of  claim 14  and a pharmaceutically acceptable carrier.