Sulfated-oxysterol and oxysterol sulfation by hydroxysterol sulfotransferase promote lipid homeostasis and liver proliferation
Inventors
Assignees
Virginia Commonwealth University • US Department of Veterans Affairs
Publication Number
US-9480692-B2
Publication Date
2016-11-01
Expiration Date
2032-04-06
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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.
Core Innovation
The invention provides methods and compositions for the prevention and treatment of liver damage or disease by increasing levels of the cholesterol metabolite 25-hydroxycholesterol-3-sulfate (25HC3S) in a subject. This can be achieved either by direct administration of 25HC3S or by overexpressing the hydroxysterol sulfotransferase enzyme SULT2B1b in the subject, which catalyzes sulfation of the endogenous substrate 25-hydroxycholesterol (25HC) to form 25HC3S. Optionally, exogenous 25HC substrate may also be administered in conjunction with the nucleic acid encoding SULT2B1b. These methodologies aim to promote lipid homeostasis and facilitate liver cell proliferation and liver tissue regeneration, and can be applied before, during, or after liver surgeries such as transplantation or partial hepatectomy.
The problem solved by the invention addresses the lack of effective treatments for liver diseases including nonalcoholic fatty liver disease (NAFLD) and other liver damage. Current options are limited, and long-term liver function absence cannot be compensated, with transplantation being the only long-term option which involves major surgery and risks. NAFLD is prevalent and characterized by lipid accumulation in liver tissue, progressing to severe liver diseases. Existing treatments improve biochemical markers but fail to reverse histological abnormalities or reduce clinical endpoints. There is a need for treatment methods to prevent or treat liver damage and promote lipid homeostasis effectively and less invasively.
The invention demonstrates that 25HC3S acts principally on the liver to regulate lipid metabolism by suppressing the liver X receptor (LXR)/sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway, thereby reducing lipid synthesis and inflammatory responses. It promotes liver regeneration by increasing hepatocyte proliferation as evidenced by increased expression of proliferative genes and proliferating cell nuclear antigen (PCNA). The methods include administration routes such as oral, intravenous, or injection, and utilize vectors, including viral vectors, to express SULT2B1b selectively in liver tissue. The methods are effective for treating liver diseases, hyperlipidemia, and related metabolic disorders.
Claims Coverage
The patent contains independent claims directed to methods for promoting hepatocyte proliferation and liver tissue regeneration in subjects undergoing liver surgery by elevating 25HC3S levels.
Elevating 25HC3S level in liver surgery subject by administering 25HC3S composition
A method of promoting hepatocyte proliferation or liver tissue regeneration in a subject undergoing liver surgery by administering a composition comprising 25HC3S and a physiologically compatible carrier during or after surgery, wherein the administered amount of 25HC3S ranges from 0.1 mg/kg to 100 mg/kg based on body mass. Administration routes include oral, enteric, sublingual, transdermal, intravenous, peritoneal, parenteral, injection, subcutaneous injection, and intramuscular injection.
Elevating 25HC3S levels to promote hepatocyte proliferation during or after liver surgery
Methods encompassing timing of elevating 25HC3S levels during or after liver surgery, including liver transplantation and partial hepatectomy, to promote hepatocyte proliferation or liver tissue regeneration in subjects needing such proliferation or regeneration.
The independent claims focus on methods of promoting liver cell proliferation or liver tissue regeneration by elevating 25HC3S levels in subjects undergoing liver surgery, through administration of 25HC3S compositions in specified dosages and various administration routes, including use during or after surgeries such as transplantation or hepatectomy.
Stated Advantages
25HC3S effectively reduces serum and hepatic lipid levels by inhibiting the LXR/SREBP-1c signaling pathway, thereby restoring lipid homeostasis.
Administration of 25HC3S protects liver function by suppressing inflammatory responses and reducing liver injury markers.
Elevating 25HC3S levels promotes hepatocyte proliferation and liver tissue regeneration, enhancing liver repair and regeneration after damage or surgery.
The methods provide non-invasive or less invasive alternatives to liver transplantation by promoting endogenous liver regeneration and lipid regulation.
Documented Applications
Prevention and treatment of liver diseases including nonalcoholic fatty liver disease (NAFLD), liver injury, hepatitis, cirrhosis, and conditions associated with excessive lipid accumulation.
Facilitation of liver tissue regeneration and hepatocyte proliferation in subjects undergoing liver surgeries such as liver transplantation and partial hepatectomy.
Treatment or prevention of hyperlipidemia and associated metabolic disorders including hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, gall stones, diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis, and metabolic syndrome.
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