Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
Inventors
Ren, Shunlin • Pandak, William M.
Assignees
Virginia Commonwealth University • US Department of Veterans Affairs
Publication Number
US-9321802-B2
Publication Date
2016-04-26
Expiration Date
2025-09-21
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The sulfated oxysterol 5-cholesten-3β, 25-diol 3-sulphate, a nuclear cholesterol metabolite that decreases lipid biosynthesis and increases cholesterol secretion and degradation, is provided as an agent to lower intracellular and serum cholesterol and/or triglycerides, and to prevent or treat lipid accumulation-associated inflammation and conditions associated with such inflammation. Methods which involve the use of this sulfated oxysterol to treat conditions associated with high cholesterol and/or high triglycerides and/or inflammation (e.g. hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver diseases, atherosclerosis, etc.) are also provided.
Core Innovation
The invention provides 5-cholesten-3β, 25-diol 3-sulphate, a novel sulfated oxysterol that functions as a nuclear cholesterol metabolite. This compound decreases lipid biosynthesis and increases cholesterol secretion and degradation, thereby lowering intracellular and serum cholesterol and triglyceride levels. It is useful for the treatment and prevention of diseases associated with elevated lipid levels and lipid accumulation-associated inflammation, including hypercholesterolemia, hypertriglyceridemia, atherosclerosis, and nonalcoholic fatty liver disease (NAFLD).
High serum lipid levels such as hypercholesterolemia and hypertriglyceridemia are linked to lipid accumulation in arterial walls, leading to conditions like NAFLD and atherosclerosis, which can result in severe cardiovascular events. Currently available lipid-lowering therapies are only effective in about 35% of patients, indicating a need for novel agents. Additionally, the progression of fatty liver disease to more severe stages involving inflammation (NASH) poses treatment challenges and risks of liver failure and cancer. There is an ongoing need for agents that reduce intracellular and serum lipids and address inflammation caused by elevated lipid levels.
The sulfated oxysterol 5-cholesten-3β, 25-diol 3-sulphate is shown to decrease lipid biosynthesis and increase cholesterol secretion and degradation, including bile acid synthesis. It is proposed to be biosynthesized in mitochondria and translocated to cell nuclei, where it regulates gene expression involved in lipid metabolism. Its natural occurrence in vivo suggests few toxic side effects. The invention also provides methods of preparing, purifying, and administering this compound, alone or in combination with existing therapies, for a range of lipid-associated and inflammatory diseases.
Claims Coverage
The patent includes two independent claims focusing on methods of decreasing fat accumulation in liver cells via administration of the compound 5-cholesten-3β, 25-diol 3-sulphate. Two main inventive features characterize these claims.
Method of decreasing fat accumulation in liver cells
Administering 5-cholesten-3β, 25-diol 3-sulphate to a patient in an amount sufficient to decrease fat accumulation in liver cells.
Method of decreasing triglyceride accumulation in liver cells
Administering 5-cholesten-3β, 25-diol 3-sulphate to a patient in an amount sufficient to decrease triglyceride accumulation in liver cells.
The claims broadly cover therapeutic methods that utilize the administration of 5-cholesten-3β, 25-diol 3-sulphate to reduce fat, including triglycerides, accumulation in liver cells, highlighting its use in treating conditions related to liver fat buildup.
Stated Advantages
Potent serum lipid lowering properties by decreasing lipid biosynthesis and increasing cholesterol secretion and degradation.
Capable of preventing or treating diseases associated with elevated lipid levels such as hypercholesterolemia, hypertriglyceridemia, NAFLD, and atherosclerosis.
Naturally occurring compound with expected minimal or no toxic side effects upon administration.
Ability to repress inflammatory responses by activating PPARγ/IκB/NFκB signaling pathway in macrophages and hepatocytes.
Demonstrated in vivo efficacy with single administration resulting in 20-40% decrease in serum cholesterol and triglycerides and significant increase in HDL.
Documented Applications
Treatment and prevention of hypercholesterolemia.
Treatment and prevention of hypertriglyceridemia.
Treatment and prevention of atherosclerosis.
Treatment and prevention of non-alcoholic fatty liver diseases (NAFLD) including fatty liver and non-alcoholic steatohepatitis (NASH).
Treatment of inflammation caused by or associated with lipid accumulation, e.g., in atherosclerosis and fatty liver diseases.
Use as a lipid-lowering medication to reduce intracellular and serum cholesterol and triglycerides.
Interested in licensing this patent?