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-11384115-B2
Publication Date
2022-07-12
Expiration Date
2025-09-21
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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 the nuclear sulfated oxysterol 5-cholesten-3β, 25-diol 3-sulphate, a nuclear cholesterol metabolite that decreases lipid biosynthesis and increases cholesterol secretion and degradation (bile acid synthesis). This sulfated oxysterol lowers intracellular and serum cholesterol and triglycerides, and prevents or treats lipid accumulation-associated inflammation and conditions associated with such inflammation, including hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver diseases (NAFLD), atherosclerosis, and related diseases.
The problem addressed is that high serum lipid levels, such as hypercholesterolemia and hypertriglyceridemia, are associated with cholesterol accumulation in arterial walls, leading to diseases like NAFLD and atherosclerosis. Current therapies for hyperlipidemia are only effective in about 35% of patients. There is an ongoing need for agents that decrease intracellular and serum lipid levels and prevent or treat disease conditions caused by inflammation resulting from elevated lipid levels.
The invention discovers that 5-cholesten-3β, 25-diol 3-sulphate is generated in mitochondria and translocates to the nucleus, where it regulates gene expression involved in cholesterol and triglyceride metabolism. It acts by decreasing lipid biosynthesis and increasing cholesterol secretion and degradation, thereby lowering lipid levels. The compound also inhibits inflammation via activation of peroxisome proliferator activator receptor gamma (PPARγ) and the PPARγ/IκB/NFκB signaling pathway. It serves as a naturally occurring LXR antagonist and PPARγ agonist, representing a new class of medication for treatment and prevention of atherosclerosis, fatty liver, diabetes, and inflammatory diseases.
Claims Coverage
The patent includes one independent claim focusing on a method to decrease fat accumulation in liver cells by intravenous administration of 5-cholesten-3β, 25-diol 3-sulphate or its pharmaceutically acceptable salts.
Method of decreasing fat accumulation in liver cells by administration of 5-cholesten-3β, 25-diol 3-sulphate
A method comprising intravenous administration of a composition comprising 5-cholesten-3β, 25-diol 3-sulphate or its pharmaceutically acceptable salt in an amount sufficient to decrease fat accumulation in liver cells of a patient in need thereof, together with a buffer and water.
Use of pharmaceutically acceptable salts to formulate 5-cholesten-3β, 25-diol 3-sulphate compositions
The composition comprises salts of 5-cholesten-3β, 25-diol 3-sulphate, including sodium, potassium, calcium, lithium, or ammonium salts, with specific embodiments emphasizing the sodium salt.
Dosage ranges and composition proportions for administration
Administration amounts range from 0.1 μg/kg/24 hours to 100 μg/kg/24 hours, with preferred ranges down to 10 μg/kg/24 hours. The composition's components (5-cholesten-3β, 25-diol 3-sulphate or salt, buffer, water) can each range from 1% to 99% of the total composition.
Treatment of patients having hepatitis
The method specifically includes patients suffering from hepatitis, administered with 5-cholesten-3β, 25-diol 3-sulphate or its salts as described.
The claims cover methods of treating fat accumulation in liver cells through intravenous administration of 5-cholesten-3β, 25-diol 3-sulphate or its salts, with defined composition ratios and dosages, and in patients with conditions such as hepatitis.
Stated Advantages
Decreases intracellular and serum lipid levels including cholesterol and triglycerides.
Increases cholesterol secretion and degradation leading to reduced lipid accumulation.
Prevents or treats diseases associated with elevated lipid levels and inflammation, including fatty liver diseases and atherosclerosis.
Acts as a naturally occurring PPARγ agonist and LXR antagonist, potentially offering fewer or no toxic side effects due to its natural occurrence.
Demonstrated significant serum cholesterol and triglyceride lowering effects in vivo after a single administration.
Documented Applications
Treatment and prevention of hypercholesterolemia, hypertriglyceridemia, gallstones, cholestatic liver disease, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), heart disease, stroke, Alzheimer's disease, inflammatory bowel diseases, diabetes (type 2 adult onset), and related inflammatory conditions caused or exacerbated by lipid accumulation.
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