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Application of MAFG as homeostatic regulation target of cholesterol and regulation agent of MAFG

A technology of cholesterol and modulators, applied in the biological field, can solve problems such as difficulty in finding alternative drugs

Active Publication Date: 2022-07-26
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, it is still difficult to find other alternative drugs in this field, and there is no effective way to solve this problem

Method used

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  • Application of MAFG as homeostatic regulation target of cholesterol and regulation agent of MAFG
  • Application of MAFG as homeostatic regulation target of cholesterol and regulation agent of MAFG
  • Application of MAFG as homeostatic regulation target of cholesterol and regulation agent of MAFG

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1. MAFG is the target gene of miR-378

[0088] In order to explore the molecular mechanism by which miR-378 regulates cholesterol and bile acid metabolism, the inventors screened the genes involved in cholesterol and bile acid metabolism targeted by miR-378 and found that the 3'UTR of MAFG contains a highly conserved gene of miR-378. binding site ( figure 1 a). Thus, miR-378 targets binding to the 3'UTR of MAFG.

[0089] The inventors cloned the 3'UTR sequence of MAFG containing the miR-378 binding site ( Figure 5 a) onto a fluorescent reporter gene (pRL-TK plasmid), and co-transfected with AgomiR-378 into 293T cells, the inventors found that overexpression of miR-378 can inhibit the fluorescence intensity of MAFG-3'UTR ( figure 1 b). However, when the binding site of miR-378 on MAFG-3'UTR was mutated, the inhibitory effect of miR-378 on MAFG-3'UTR fluorescence intensity disappeared ( figure 1 c).

[0090] Mut1: put the 5'-AGUC C AG-3' segment was mutate...

Embodiment 2

[0094] Example 2. Inhibition of MAFG in the liver can reduce serum cholesterol levels and promote the synthesis and excretion of bile acids

[0095] Although MAFG was found to inhibit bile acid synthesis, whether MAFG can affect cholesterol metabolism still needs further exploration. The inventors constructed a shRNA plasmid against MAFG and further constructed an adenovirus ( figure 2 a).

[0096] Taking pENTR-U6 as the backbone plasmid, the shRNA sequence inserted into the plasmid is:

[0097] 5'-GCCACCAGCGTCATCACAATACGAATATTGTGATGATGACGCTGGTGGC-3' (SEQ ID NO: 5).

[0098] The inventors found that after inhibiting the expression of MAFG in the liver, the serum cholesterol level was significantly decreased ( figure 2 b), and both serum low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels were significantly reduced ( figure 2 c), indicating that MAFG may mediate the regulatory effect of miR-378 on cholesterol. The inventor...

Embodiment 3

[0101] Example 3. Overexpression of MAFG in the liver inhibits bile acid synthesis and increases serum cholesterol levels

[0102] The inventors constructed an adenovirus ( Figure 4 a), it was found that after overexpression of MAFG in mouse liver, the cholesterol level in mouse serum was significantly increased ( Figure 4 b).

[0103] The inventors further found that after overexpression of MAFG in the liver, the RNAs of CYP7B1, CYP8B1 and CYP27A1 ( Figure 4 c) and protein ( Figure 4 d) The expression levels were significantly decreased, but the expression levels of CYP7A1 did not change significantly ( Figure 4 c-d). Consistent with this, the inventors also found in primary hepatocytes that the RNAs of CYP7B1, CYP8B1 and CYP27A1 ( Figure 4 e) and protein ( Figure 4 f) The expression levels were significantly decreased, but the expression levels of CYP7A1 did not change significantly ( Figure 4 e-f).

[0104] These findings suggest that overexpression of MAFG ...

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Abstract

The invention reveals that the V-Maf bird myofascia fibrosarcoma cancer gene homolog G (MAFG) is a regulation target of cholesterol homeostasis, and the MAFG and a regulator thereof can be used as a new way for developing drugs for high cholesterol related diseases (such as hypercholesterolemia and atherosclerosis) or low cholesterol related diseases.

Description

technical field [0001] The present invention belongs to the field of biotechnology, and more particularly, the present invention relates to the application of MAFG as a target for regulating cholesterol homeostasis and a regulator thereof. Background technique [0002] Cholesterol is not only an important component of cell membranes, but also a precursor to steroid hormones and bile acids in the body. It is important to maintain a homeostasis of cholesterol in the body because excessive serum cholesterol levels increase the risk of atherosclerosis and cardiovascular disease. The body maintains the balance of cholesterol homeostasis mainly through the uptake, de novo synthesis and metabolism of cholesterol into bile acids. [0003] Thyroid hormone (TH) plays a role in the regulation of cholesterol and bile acid metabolic homeostasis in the body. Studies have found that hyperthyroidism is associated with increased hepatic cholesterol excretion and decreased serum cholesterol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K48/00A61K31/7088A61P3/06A61P9/10C12Q1/6883G01N33/68C12Q1/02
CPCA61K45/00A61K31/7088A61P3/06A61P9/10C12Q1/6883G01N33/6893G01N33/5038G01N2500/02G01N2500/04G01N2800/323G01N2800/044C12Q2600/136C12Q2600/158G01N2500/10
Inventor 应浩孙超刘威吴玉婷
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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