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CN-122028923-A - Use of coagulation promoting factors in regulating lipid homeostasis

CN122028923ACN 122028923 ACN122028923 ACN 122028923ACN-122028923-A

Abstract

The present application relates to methods, compounds and compositions for promoting cell COPII aggregation in a subject, modulating plasma lipids in a subject, or treating or preventing a disease, disorder or condition associated with or caused by dyslipidemia, chylomicron retention disease or symptoms thereof.

Inventors

  • CHEN XIAOWEI
  • WANG XIAO
  • WANG YAWEI

Assignees

  • 北京大学

Dates

Publication Date
20260512
Application Date
20240909
Priority Date
20230908

Claims (20)

  1. 1. A method of reducing plasma lipids in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a coagulation promoting factor.
  2. 2. The method of claim 1, wherein the agglomeration promoting factor is manganese.
  3. 3. The method of claim 2, wherein the manganese is provided in the form of divalent manganese.
  4. 4. A method according to claim 3, the divalent manganese being provided in the form of manganese chloride, manganese nitrate, manganese sulphate, manganese acetate, manganese thiocyanate, manganese stearate or manganese ascorbate.
  5. 5. The method of any one of claims 2 to 4, wherein the manganese is administered in addition to manganese present in the normal diet of the subject.
  6. 6. The method of any one of claims 2 to 5, wherein the amount of manganese administered is about 0.01-100 mg/kg of subject body weight, preferably 0.02-80 mg/kg of subject body weight, more preferably 0.03-60 mg/kg of subject body weight, even more preferably 0.04-50 mg/kg of subject body weight.
  7. 7. The method of claim 6, wherein the administration is daily.
  8. 8. The method of any one of claims 2 to 7, wherein the manganese is administered in an amount about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold greater than the manganese present in the normal diet of the subject.
  9. 9. The method of any one of claims 1 to 8, further comprising administering a mitochondrial uncoupling agent.
  10. 10. The method of claim 9, wherein the mitochondrial uncoupling agent is carbonyl cyanidate p-trifluoromethoxybenzohydrazone or 2, 4-dinitrophenol.
  11. 11. The method of any one of claims 1 to 11, wherein the plasma lipid is an atherogenic lipid.
  12. 12. The method of claim 11, wherein the atherogenic lipids comprise one or more of Low Density Lipoprotein (LDL) -cholesterol (LDL-C), very Low Density Lipoprotein (VLDL) -cholesterol (VLDL-C), medium density lipoprotein (IDL) -cholesterol (IDL-C), non-high density lipoprotein (non-HDL) -cholesterol (non-HDL-C), apolipoprotein B (APOB), APOB-containing lipoproteins and triglycerides.
  13. 13. The method of any one of claims 1 to 12, wherein the subject has atherosclerosis, risk of developing atherosclerosis, hypercholesterolemia, dyslipidemia, coronary heart disease, history of coronary heart disease, premature coronary heart disease, risk of developing coronary heart disease, type II diabetes with dyslipidemia, hypertriglyceridemia, hyperlipidemia, hepatic steatosis, nonalcoholic steatohepatitis, or nonalcoholic fatty liver disease.
  14. 14. A method of reducing plasma lipids in a subject in need thereof, comprising inhibiting expression of a gene encoding a mitochondrial calcium unidirectionally transporter (MCU).
  15. 15. The method of claim 14, wherein gene suppression is achieved by gene editing based on a gene nuclease.
  16. 16. A method of treating or preventing dyslipidemia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a coacervation promoting factor, preferably manganese, more preferably divalent manganese.
  17. 17. A method of treating or preventing a disease, disorder or condition associated with or caused by dyslipidemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a condensation promoting factor, preferably manganese, more preferably divalent manganese.
  18. 18. The method of claim 17, wherein the disease, disorder or condition associated with or caused by dyslipidemia may be cardiovascular disease (CVD) or atherosclerotic cardiovascular disease (ASCVD).
  19. 19. A method according to any one of claims 16 to 18, wherein the divalent manganese is provided in the form of manganese chloride, nitrate, sulphate, acetate, thiocyanate, stearate or ascorbate.
  20. 20. The method of any one of claims 16 to 19, wherein the divalent manganese is administered in addition to divalent manganese present in the normal diet of the subject.

Description

Use of coagulation promoting factors in regulating lipid homeostasis Cross Reference to Related Applications The present application claims priority from PCT patent application No. PCT/CN2023/117698 filed on 89 2023, entitled "use of coagulation promoting factors in regulating lipid homeostasis" and claims PCT patent application No. USE OF CONDENSATION-PROMOTING FACTOR IN REGULATING LIPID HOMEOSTASIS. Technical Field The present disclosure is in the field of lipid modulation. In particular, the present invention relates to methods and compositions for modulating circulating lipids by modulating the level of a coagulation promoting factor, such as manganese ions. Background Precise control of circulating lipids (particularly the amount of lipoproteins transporting lipids) is critical for health and disease control. COPII the complex preferentially secretes lipoproteins into the circulation by self-constrained coacervation, which balances assembly and dynamics to obtain maximum output. However, the means of modulating biomolecular condensation to achieve key physiological outcomes or disease treatments remain limited. Despite great progress in understanding its etiology and in developing therapeutic approaches, atherosclerotic cardiovascular disease (ASCVD) and related metabolic complications remain the first killers of modern society. Dyslipidemia is the most common risk factor and major therapeutic target for ASCVD. A large number of lipids, including triglycerides and cholesterol, are transported into the blood stream by lipoproteins containing apolipoprotein B (APOB), which initially assemble in the lumen of the Endoplasmic Reticulum (ER), and subsequently open the secretory pathway into the circulation. Notably, an increased number of lipoproteins containing apolipoprotein B in the circulation carries a higher risk of CVD than an increase in blood lipids per se. However, precise control of the secretory process of lipoproteins into the circulation has yet to be fully elucidated, especially in comparison to our understanding of uptake and clearance of lipoproteins from the circulation. Coat protein complex II (COPII) controls the entry of the secretory pathway at the surface of the endoplasmic reticulum, creating a transport vesicle to shuttle numerous cargo that vary greatly in nature and quantity. COPII assembly and cargo packaging begins with activation of small gtpase SAR1, which recruits inner coated heterodimer SEC23/SEC24 followed by outer coated heterotetramer SEC31/SEC13 interacting with the inner coating. SAR1 interacts directly with SEC23, whereas SEC24 binds transmembrane cargo or cargo receptors that mediate selective transport events. Consistent with this general paradigm, SAR1 paralogs SAR1B pair with COPII cargo receptor SURF4 to drive a high capacity but selective endoplasmic reticulum export program of lipoproteins. Furthermore, SAR1B mutation causes the patient to suffer from a rare disease, chylomicron retention disease (CMRD), while the genetic polymorphism of SURF4 is closely related to human plasma lipid levels, which together underscores the relevance of lipoprotein secretion to human disease. COPII subunit SEC24 responsible for cargo selection contains Intrinsic Disorder Regions (IDR) of unknown character, which may undergo dynamic multivalent interactions to drive protein aggregation and promote cellular tissue and biological responses. For lipoprotein transport, COPII complexes are able to undergo self-constrained aggregation in a manner that depends on the intrinsic disordered region, thereby maximizing the efficiency of coating assembly while maintaining optimal dynamics of vesicle generation. In addition, this unconventional mechanism is exploited genetically at the level of SEC16A in humans, SEC16A defining a dose-sensitive secretory program to selectively mediate lipoprotein transport, unlike general secretory programs. However, the effective means of precisely modulating the aggregation-based lipoprotein delivery to achieve lipid control remains limited, particularly under physiological or even pathological conditions. Cardiovascular disease (CVD) and related metabolic disorders remain a major cause of death in humans, leading to over 2000 tens of thousands of deaths worldwide each year. Hyperlipidemia or elevated levels of circulating lipids are major risk factors for CVD, particularly by inducing atherosclerosis. Although the formation of atherosclerotic plaques is a lengthy process, unstable plaques are prone to rupture and hemorrhage, causing acute thrombosis, which may lead to life-threatening myocardial infarction or stroke. Notably, atherosclerotic plaques tend to be clinically "silent" in their initial stages and are therefore often not perceived by the patient. In this case, an effective means of safely reversing existing atherosclerotic plaques would be of great therapeutic interest. Unfortunately, to date, such methods have yet to be established, representing a