Sulfated-Oxysterol and Oxysterol Sulfation by Hydroxysterol Sulfotransferase Promote Lipid Homeostasis and Liver Tissue Regeneration

Abstract

Methods and compositions for the prevention and treatment of liver damage or disease in a subject in need thereof are provided. The methods involve providing the sulfated oxysterol 25-hydroxycholesterol-3-sulfate (25HC3S) to the subject e.g. by 1) administering 25HC3S to the subject; or 2) overexpressing, in the subject, the hydroxysterol sulfotransferase enzyme SULT2B1b, which catalyzes the sulfation of 25-hydroxycholesterol (25HC) to form 25HC3S.

1 . A method for promoting liver cell proliferation or liver tissue regeneration in a subject, comprising:
 elevating a level of 25-hydroxycholesterol-3-sulfate (25HC3S) in a subject in need of at least one of liver cell proliferation and liver tissue regeneration in order to promote proliferation of liver cells or regeneration of liver tissue in said subject.   
     
     
         2 . The method of  claim 1  wherein said elevating a level of 25HC3S is performed by administration of exogenous 25HC3S to said subject. 
     
     
         3 . The method of  claim 2  wherein the 25HC3S is administered in an amount ranging from 0.1 mg/kg to 100 mg/kg, based on body mass of said subject. 
     
     
         4 . The method of  claim 2  wherein the 25HC3S is administered in an amount ranging from 1 mg/kg to 10 mg/kg, based on body mass of said subject. 
     
     
         5 . The method of  claim 2  wherein the administration comprises at least one of oral administration, enteric administration, sublingual administration, transdermal administration, intravenous administration, peritoneal administration, parenteral administration, administration by injection, subcutaneous injection, and intramuscular injection. 
     
     
         6 . The method of  claim 1  wherein said elevating a level of 25HC3S is performed by providing hydroxycholesterol sulfotransferase 2B1b (SULT2B1b) and 25-hydroxycholesterol (25HC) to said subject. 
     
     
         7 . The method of  claim 1  wherein said elevating a level of 25HC3S is performed by promoting overexpression of SULT2B1b in said subject and providing 25HC to said subject. 
     
     
         8 . The method of  claim 1  wherein said elevating is performed before, during or after liver surgery in said subject. 
     
     
         9 . The method of  claim 8  wherein the liver surgery comprises liver transplant surgery. 
     
     
         10 . The method of  claim 1  wherein said subject has at least one of cirrhosis, liver injury, and hepatitis. 
     
     
         11 . The method of  claim 1  wherein said elevating is performed using a viral vector comprising a nucleic acid sequence coding for SULT2B1b. 
     
     
         12 . A method for promoting liver regeneration, comprising:
 administering to a subject a nucleic acid sequence coding for SULT2B1b, wherein said administering is performed such that said nucleic acid sequence is selectively expressed in liver cells in said subject.   
     
     
         13 . The method of  claim 12  wherein said administering is performed before, during or after liver surgery in said subject. 
     
     
         14 . The method of  claim 13  wherein the liver surgery comprises liver transplant surgery. 
     
     
         15 . The method of  claim 12  wherein said subject has at least one of cirrhosis, liver injury, and hepatitis. 
     
     
         16 . The method of  claim 12  wherein said administering is performed using a viral vector. 
     
     
         17 . A method for treating or preventing hyperlipidemia or fatty liver disease or malady resulting from hyperlipidemia or fatty liver disease, comprising:
 providing a subject with a sufficient amount of a sulfotransferase to elevate endogenous levels of 25HC3S in said subject, wherein said elevated endogenous levels of 25HC3S are sufficient to decrease lipid synthesis in said subject so as to reduce serum and hepatic lipid levels in said subject, or to reduce one or more regulators of lipid metabolism in said subject.   
     
     
         18 . The method of  claim 17  wherein said sulfotransferase is SULT2B1b. 
     
     
         19 . The method of  claim 17  wherein said providing is performed by administering said subject a nucleic acid sequence coding for SULT2B1b, wherein said administering is performed such that said nucleic acid sequence is expressed in liver cells in said subject. 
     
     
         20 . The method of  claim 19  further comprising administering 25HC to said subject. 
     
     
         21 - 25 . (canceled)