CN-121971610-A - Use of Fn1-PPAR beta/delta signal pathway in relation to cardiac liver disease

Abstract

The invention discloses an application of Fn1-PPAR beta/delta signal channel related to cardiac liver diseases. According to the invention, a heart-derived liver disease model is constructed according to the liver development retardation of young individuals and the severe fatty liver of adult and young individuals caused by heart injury. In this model, fn1 protein levels in the heart and blood were found to be significantly elevated compared to normal levels. Based on zebra fish cardiac ablation means, heart specific knock-down Fn1 can lead to reduction of Fn1 protein level in blood, and slow liver development and alleviation of fat deposition after cardiac ablation injury. Through transcriptomic screening, we found that pparβ/δ protein in the liver was a potential downstream effector of Fn 1. The liver-specific over-expression of PPARbeta/delta protein can obviously relieve abnormal phenotypes such as liver fat deposition and the like caused by heart injury, and after the liver-specific PPARbeta/delta protein is knocked down, the liver protection effect of knock-down Fn1 on the liver is eliminated under the heart injury condition. Therefore, fn1 protein and PPAR beta/delta protein can be used as cardiac liver injury control targets for preparing medicaments for improving cardiac liver injury, thereby providing a new way for treating cardiac liver diseases.

Inventors

• ZHANG RUILIN
• LV HONGBO
• LIU HUANYU
• GAO PENG
• Xiang Shupeng
• LIU YANMEI
• LI QI

Assignees

• 武汉大学

Dates

Publication Date

20260505

Application Date

20251218

Claims (9)

1. 1. Use of an agent that targets the Fn1-pparβ/δ pathway in the manufacture of a medicament for treating liver disease in a subject in need thereof, wherein the agent that targets the Fn1-pparβ/δ pathway is an Fn1 inhibitor or a pparβ/δ activator.
2. 2. The use according to claim 1, wherein the liver disease is a cardiac injury-induced liver disease.
3. 3. The use according to claim 2, wherein the liver disease is cardiac injury induced liver hypoevolutism and fat deposition.
4. 4. The use according to claim 2, wherein the liver disease is a cardiac injury-induced fatty liver disease.
5. 5. The use according to any one of claims 1 to 4, wherein the agent targeting the Fn1-pparβ/δ pathway is an Fn1 inhibitor, which Fn1 inhibitor is a gene editing system, antisense oligonucleotide, shRNA or siRNA targeting the coding sequence of Fn 1.
6. 6. The use according to any one of claims 1 to 4, wherein the agent targeting the Fn1-pparβ/δ pathway is a pparβ/δ activator that delivers the coding sequence of pparβ/δ by targeting a carrier, which is an AAV vector or a lipid nanoparticle.
7. 7. The use according to any one of claims 1-6, wherein the subject is a human and the Fn1 is human Fn1.
8. 8. A method of screening for a drug for preventing or treating liver disease comprising detecting the interaction of a compound with Fn1 or pparβ/δ, wherein said interaction inhibits or blocks Fn1 or enhances pparβ/δ mediated signaling pathways.
9. 9. The method of claim 8, wherein the model animal used for the detection is zebra fish.

Description

Use of Fn1-PPAR beta/delta signal pathway in relation to cardiac liver disease Technical Field The invention relates to the field of functions and technical application of proteins, in particular to application of Fn1-PPAR beta/delta signal channels to cardiac liver diseases. Background Myocardial infarction (myocardial infarction, MI) has a high global incidence, severely threatening human health, and the cardiomyocytes die in the process, leading to permanent damage to the heart and ultimately Heart Failure (HF). Progression of heart disease often results in physiological disturbances of systemic organs, and the occurrence of systemic complications not only increases the health burden of the patient, but also greatly increases the mortality rate of heart disease patients, suggesting that a mechanism for organ-to-organ communication is essential. The liver is an important regulating organ of the body's energy homeostasis, playing an important role in glucose and lipid metabolism. Clinical studies have shown that there is a bi-directional interaction between the heart and liver, and that heart related diseases can lead to the development of liver diseases which can also induce or exacerbate heart dysfunction. The path of heart disease promotion of liver disease progression can be summarized as being due to macroscopic hemodynamic changes including hypoxia, hyperemia and blood flow disturbances on the one hand and being closely related to the function of the heart as an endocrine organ on the other hand. In recent years, the heart has been demonstrated to secrete a series of active factors such as GDF15, myostatin, ANP/BNP, which means that the effect on the liver is superior to the traditional "pumping blood" category, and a heart-derived "heart-liver axis" endocrine regulation network is formed. These secreted factors maintain basal expression in healthy hearts, and their levels are markedly elevated in cardiovascular diseases such as heart failure and heart ischemia/reperfusion. The role of extracellular matrix in tissue injury is far beyond providing structural support and mechanical properties, whose dynamic interactions with cells actively regulate key cellular processes such as proliferation, migration and differentiation. As a core component of the extracellular matrix, fibronectin1 (Fn 1) plays a complex signaling molecule role in physiological processes such as development and wound repair. Studies have shown that in the adult zebra fish heart regeneration model, the injured epicardial cells can dynamically synthesize and secrete Fn1, a process critical for heart regeneration. In addition, kuramoto et al studies revealed that exercise induces skeletal muscle secretion FN1 into the circulation, activating liver autophagy via the FN1- α5β1 integrin signaling axis, thereby exerting liver protection. These findings raise a key scientific question that is not yet clear, whether Fn1 generated after cardiac injury can be used as a circulatory signal to remotely regulate the physiological state of other organs. Disclosure of Invention The inventors found that Fn1 secreted after acute cardiac injury is associated with pathological processes in the liver, pparβ/δ protein in the liver being a downstream effector of Fn 1. Based on the above, the invention aims to provide an application of an Fn 1-PPARbeta/delta pathway targeting agent in preparing medicaments for treating heart-derived liver disease processes, and an application of Fn1 protein or PPARbeta/delta protein serving as a medicament target in screening medicaments for treating liver pathological processes. The above purpose is achieved by the following technical scheme: The invention adopts myocardial specificity ablation zebra fish strain Tg (vmhc: mCherry-NTR). The strain integrates a bacterial nitroreductase gene into the zebra fish genome by using a genetic engineering technology, and realizes specific expression in ventricular cells through a ventricular myosin heavy chain promoter. In this system, metronidazole can be metabolized by nitroreductase, converted to a product with strong cytotoxicity, causing DNA damage and rapidly leading to cardiomyocyte death, thus constructing a rapid heart damage model. In this model, it was found that heart damage resulted in liver development retardation in young zebra fish, and liver fat deposition occurred in both young and adult zebra fish. Transcriptome analysis showed significant enrichment of extracellular matrix (ECM) -related signaling pathways in the heart following cardiac injury. And further, the expression of fibronectin 1 (Fn 1) in heart tissues after injury and the level of Fn1 protein in serum are obviously increased through the combined verification of transcriptome data and experiments. To explore the role of Fn1 therein, we established a transgenic line Tg (cmlc: cas9-T2A-EGFP; U6: sg-Fn1a; U6: sg-Fn1 b) (abbreviated as KD-Fn 1) for heart-specific knock-down of Fn 1. The strain expresses Cas