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-9034859-B2
Publication Date
2015-05-19
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 the level of the cholesterol metabolite 25-hydroxycholesterol-3-sulfate (25HC3S) in a subject in need thereof. This increase can be achieved either by administering 25HC3S directly or by overexpressing the hydroxysterol sulfotransferase enzyme SULT2B1b in the subject, which catalyzes the sulfation of the endogenous substrate 25-hydroxycholesterol (25HC) to form 25HC3S.
The liver plays a pivotal role in metabolism and lipid homeostasis. Liver damage occurs due to various causes such as toxins, alcohol consumption, obesity, high-fat diets, viral infections, hereditary factors, cancer, medication use, and trauma. Nonalcoholic fatty liver disease (NAFLD) is a major concern, characterized by lipid accumulation in the liver and associated with obesity, inflammation, cirrhosis, and hepatocellular carcinoma. Current treatments do not effectively reverse histological abnormalities, and liver transplantation is the only long-term solution but involves major surgery and risk of rejection.
The problem solved by this invention is the lack of effective methods to prevent or treat liver damage such as NAFLD and to promote lipid homeostasis. The invention addresses this by utilizing the sulfated oxysterol 25HC3S or by enhancing its biosynthesis via SULT2B1b overexpression. The compounds act on liver function to both prevent and treat liver diseases and diseases associated with hyperlipidemia.
Claims Coverage
The patent includes one independent claim related to a method for promoting liver cell proliferation or liver tissue regeneration by elevating 25HC3S levels in a subject without hyperlipidemia.
Method for promoting liver cell proliferation or liver tissue regeneration by elevating 25HC3S
A method comprising identifying a subject in need of liver cell proliferation or liver tissue regeneration and elevating the level of 25-hydroxycholesterol-3-sulfate (25HC3S) in the subject by administering a composition comprising 25HC3S and a physiologically compatible carrier, wherein the subject does not have hyperlipidemia. The elevating promotes proliferation or regeneration of liver cells or tissue.
Administration parameters for 25HC3S
Administering 25HC3S in an amount ranging from 0.1 mg/kg to 100 mg/kg, or alternatively, from 1 mg/kg to 10 mg/kg, based on the body mass of the subject.
Modes of administration for 25HC3S
Administration of 25HC3S comprises at least one of oral, enteric, sublingual, transdermal, intravenous, peritoneal, parenteral, injection, subcutaneous, and intramuscular routes.
Application timing with respect to liver surgery
Elevating 25HC3S levels may be performed before, during, or after liver surgery, including liver transplant surgery.
Treatment of subjects with liver conditions
Method applies to subjects with liver injury, hepatitis, viral hepatitis, autoimmune hepatitis, or liver inflammation caused by virus, poison, drugs (including amiodarone, antiviral drugs, aspirin, corticosteroids, methotrexate, tamoxifen, tetracycline), or hereditary conditions.
The independent claim provides a method of promoting liver cell proliferation or liver tissue regeneration in subjects without hyperlipidemia through administration of 25HC3S in specified doses and by various administration routes, applicable before, during, or after liver surgery and to subjects with various liver injuries or inflammatory conditions.
Stated Advantages
25HC3S effectively lowers serum and hepatic lipid levels in mouse models of nonalcoholic fatty liver disease (NAFLD) by suppressing key gene expressions involved in lipid biosynthesis.
Administration of 25HC3S suppresses hepatic inflammation and protects the liver from injury.
Overexpression of SULT2B1b increases 25HC sulfation, reduces serum and hepatic triglycerides and cholesterol, and regulates lipid metabolism.
25HC3S and SULT2B1b promote liver cell proliferation and liver tissue regeneration by increasing proliferative gene expression and DNA replication.
The methods inhibit liver X receptor (LXR) signaling leading to favorable lipid homeostasis and enhanced liver regeneration.
Treatment reduces liver damage markers and inflammatory cytokines associated with liver disease.
Documented Applications
Prevention and treatment of liver diseases including nonalcoholic fatty liver disease (NAFLD), liver injury, hepatitis, cirrhosis, and liver inflammation caused by viruses, poisons, drugs, or hereditary conditions.
Facilitating recovery and liver regeneration after liver surgeries including hepatectomy and liver transplantation.
Treatment or prevention of hyperlipidemia and lipid-related disorders including hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, atherosclerosis, stroke, gall stones, diabetes, inflammatory bowel disease, and nonalcoholic steatohepatitis.
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