CN116098988A - Application of ALDH2 protein in medicine for preventing and/or treating non-alcoholic fatty liver disease - Google Patents
Application of ALDH2 protein in medicine for preventing and/or treating non-alcoholic fatty liver disease Download PDFInfo
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Abstract
The invention discloses an application of ALDH2 protein in a medicament for preventing and/or treating non-alcoholic fatty liver disease, which belongs to a new application of ALDH2 protein, and prevents and treats MCD-induced non-alcoholic fatty liver disease by activating ALDH2 specifically by ALda-1; the specific agonist alda-1 of ALDH2 is prepared into injection in the form of pharmaceutically acceptable excipient/carrier, and is subjected to intermittent subcutaneous injection to excite the activity of ALDH 2. The invention discovers the brand new key effect of ALDH2 protein in the non-alcoholic fatty liver disease for the first time, and agonizes the ALDH2 to relieve the non-alcoholic fatty liver disease, thereby having wide clinical application prospect.
Description
Technical Field
The invention relates to a novel application of ALDH2 protein, in particular to an application of ALDH2 protein in medicines for preventing and/or treating nonalcoholic fatty liver disease.
Background
Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of at least 5% of liver steatosis, but the lack of common causes of secondary liver fat accumulation, such as excessive alcohol consumption, chronic viral hepatitis, autoimmune hepatitis, congenital liver disease or long-term use of steatosis-inducing drugs. NAFLD is often (but not always) concurrent with type 2 diabetes, obesity, dyslipidemia and hypertension, which constitute a metabolic disorder of the heart. The global prevalence of NAFLD is estimated to be 25.24%, with the highest incidence in the middle east (31.79%) and south america (30.45%), followed by asia (27.37%), north america (24.13%), europe (23.71%) and africa (13.48%). NAFLD incidence rates in different countries are reported to range from 20 to 50 per 1000 years. These striking numbers make NAFLD a major clinical and economic burden and a new epidemic of chronic liver disease worldwide. Most patients with NAFLD develop non-alcoholic steatohepatitis (NASH), which is histologically characterized by the presence of liver inflammation and liver injury. NAFLD, and in particular NASH, may develop fibrosis, cirrhosis, and eventually hepatocellular carcinoma. In this context NAFLD is currently the leading cause of chronic liver disease worldwide. NASH-related cirrhosis has become the second major indication for adult liver transplantation in the united states and continues to grow.
The pathogenesis of NAFLD is currently poorly understood. It is thought that this involves complex interactions between genetic susceptibility variations, environmental factors, insulin resistance and changes in intestinal flora. Interactions between these factors lead to alterations in lipid metabolism and excessive accumulation of lipids in hepatocytes, ultimately leading to the development of NAFLD. Thus, there is an urgent need to fully understand the pathogenesis of NAFLD, which may help to improve diagnosis, patient typing and to identify new therapeutic targets.
Human ALDH2 is a 517 amino acid polypeptide encoded by a nuclear gene located at chromosome 12q 24. Proteins are transported to the mitochondrial matrix in a process that depends on their NH2 terminal 17-amino acid mitochondrial targeting sequence, which is cleaved during complete folding and maturation of enzymes within the centrosome. Like most members of the ALDH family, ALDH2 is a tetrameric enzyme having the same subunit of 56 kDa. Tetramers are considered dimers of dimers, with only 2 catalytic sites on each enzyme complex remaining active. Each subunit consists of three major domains: catalytic domain, coenzyme or NAD binding domain, and an oligomerization domain. In addition to its dehydrogenase activity, ALDH2 also has reductase and esterase activities. ALDH2 is ubiquitously expressed in all tissues, but is most abundant in the liver and is also found in large numbers in organs (e.g., heart and brain) where high mitochondrial oxidative phosphorylation is required.
The key role of ALDH2 in ethanol metabolism is known. The detoxification pathway of ethanol in the human body occurs mainly in the liver and proceeds through two enzymatic steps. The first step is catalyzed by Alcohol Dehydrogenase (ADH) and the second step is catalyzed primarily by ALDH 2. Of the 19 human ALDH isozymes, ALDH2 is the most potent enzyme for alcohol-derived acetaldehyde metabolism. In humans, ALDH2 may be the only significant contributor to ALDH enzyme. Acetaldehyde metabolism. It is well known that ALDH2 is also capable of metabolizing many other short chain aliphatic aldehydes, as well as some aromatic and polycyclic aldehydes, thereby providing important protective enzymatic functions against these toxic substances. In particular, ALDH2 plays a key role in endogenous hydroformylation products produced by lipid peroxidation under oxidative stress, such as 4-hydroxy-2-nonenal (4-HNE) and Malondialdehyde (MDA) as well as environmental aldehydes, such as acrolein (e.g., tobacco smoke and automobile exhaust).
The genetic polymorphism of human ALDH2 has been well investigated in a broad population of ethnicities. The most relevant ALDH2 variants are ALDH2 x 2 alleles found in up to 35% to 45% of eastern asians (i.e., chinese, japanese, korean). The ALDH2 enzyme activity of ALDH2 carriers is low, and the symptoms of facial flushing, headache, nausea, dizziness and palpitation, which occur after eating alcoholic beverages, can compensate for this deficiency. This alcohol-induced flushing syndrome in ALDH2 x 2 individuals is caused by a single G-to-nucleotide change, which results in substitution of glutamic acid to lysine at position 48. The E487K mutation has a dominant effect compared to the wild type monomer encoding the ALDH2 x 1 allele. Thus, heterozygous individuals (ALDH 2 x 1/. Times.2) were significantly less active than wild-type 50%, whereas homozygotes of ALDH2 x 2/. Times.2 had only 1-4% of wild-type. And (3) activity. In the case of 5.6 billion (or 8%) of people worldwide suffering from this mutation, ALDH2 x 2 is probably the most common human enzyme deficiency, exceeding other well-known human enzyme diseases. Notably, all 5.6 million eastern asians carry the same single nucleotide mutation. There are few studies on the relationship of ALDH2 to non-alcoholic liver disease, essentially focusing on statistics, and several statistics show that high alcohol consumption by those carrying ALDH2 mutant genotypes will significantly increase the risk of non-alcoholic fatty liver disease.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide the application of ALDH2 protein in medicaments for preventing and/or treating non-alcoholic fatty liver disease.
The technical scheme of the invention is summarized as follows:
use of ALDH2 protein in the manufacture of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease.
Further, the ALDH2 is specifically activated by the alda-1 to prevent and treat the non-alcoholic fatty liver disease induced by the MCD.
Furthermore, the specific agonist alda-1 of ALDH2 is prepared into injection in the form of pharmaceutically acceptable excipient/carrier, and is subjected to intermittent subcutaneous injection to excite the activity of ALDH 2.
Further, the non-alcoholic fatty liver disease is a non-alcoholic fatty liver disease.
The invention has the beneficial effects that:
1. the invention discovers the brand new key effect of ALDH2 protein in the non-alcoholic fatty liver disease for the first time, and agonizes the ALDH2 to relieve the non-alcoholic fatty liver disease, thereby having wide clinical application prospect.
2. The invention relates to a medicament for preventing and/or treating non-alcoholic fatty liver disease, which comprises a specific agonist alda-1 of ALDH2, a modified ALDH2 protein comprising an active ingredient, and medicinal excipients and carriers thereof, wherein the specific agonist alda-1 of the ALDH2 can be prepared into injection in the form of the medicinal excipients/carriers for intermittent subcutaneous injection to excite the activity of the ALDH2 and protect the non-alcoholic fatty liver disease in clinical treatment of the ALDH 2.
Drawings
FIG. 1 is a graph showing the effect of ALDH2 deficiency in high-fat diet and western diet-induced NAFLD;
FIG. 2 is a graph showing the effect of ALDH2 deficiency on liver of MCD diet-induced NASH mice;
FIG. 3 is a graph showing the effect of ALDH2 deficiency on MCD diet-induced inflammatory factors in NASH mice;
FIG. 4 is a graph showing the effect of Alda-1, an ALDH2 specific activator, on liver of MCD diet-induced NASH mice;
FIG. 5 is a graph showing the effect of Alda-1, an ALDH 2-specific activator, on inflammatory factors in NASH mice induced by MCD diet.
Detailed Description
The present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
Example 1
Serum Triglyceride (TG) and inflammatory factor (CRP, TNF-. Alpha., MCP-1, IL-1-. Beta., IL-6) levels were examined after 8 weeks of feeding the mice deficient in the ALDH2 gene and wild type respectively with a High Fat Diet (HFD) and a Western Diet (WD) to induce a non-alcoholic fatty liver (NAFLD) model, as shown in FIG. 1.
The experimental results show that: the ALDH2 deficiency significantly aggravates the accumulation of triglycerides and the level of serum inflammatory factors in the non-alcoholic fatty liver (NAFLD) mouse model, suggesting that ALDH2 deficiency aggravates the lipid accumulation and the level of inflammation in the NAFLD mouse model.
Example 2
The mice deficient in ALDH2 gene and wild type were fed with methionine-choline deficiency (MCD) diet, NASH mouse model was induced, and serum inflammatory factor levels of mice were further examined.
As shown in fig. 2, ALDH2 deletion significantly aggravated the degree of fat accumulation and liver damage in NASH mice, and was found to be consistent with the liver pathological phenotype by detecting the levels of inflammatory factors in the serum of the mice; as shown in fig. 3, ALDH2 deletion significantly increased the inflammatory level in NASH mice, suggesting that ALDH2 deletion also significantly aggravates liver injury in NASH mice.
Example 3
The experimental result shows that the ALDH2 specific activator Alda-1 is injected into the abdominal cavity of a wild mouse: alda-1 significantly reduced liver fat accumulation in NASH mice (FIGS. 4A, B); alda-1 significantly reduced serum triglyceride levels and transaminase levels (fig. 4c, d), suggesting that specific activation of ALDH2 can significantly alleviate NASH, and detect levels of serum inflammatory factors in mice, found to be consistent with liver pathology results; alda-1 significantly reduced serum inflammatory levels in NASH mice (FIG. 5). Thus, ALDH2 functions biologically mainly by its enzymatic activity, and it is speculated that enhancing ALDH2 enzymatic activity may alleviate liver injury in NASH mice.
The embodiment discovers the brand new key effect of the ALDH2 protein in the non-alcoholic fatty liver disease for the first time, and the activation of the ALDH2 can relieve the non-alcoholic fatty liver disease and has wide clinical application prospect.
The above examples relate to a medicament for preventing and/or treating non-alcoholic fatty liver disease, comprising ALDH2 specific agonist alda-1 and modified ALDH2 protein comprising active ingredient and pharmaceutical excipient, carrier thereof, as medicament for preventing and/or treating non-alcoholic fatty liver disease, clinical treatment of ALDH2 can be achieved by preparing ALDH2 specific agonist alda-1 into injection in the form of pharmaceutical excipient/carrier, and performing intermittent subcutaneous injection to activate ALDH2 activity, thereby protecting non-alcoholic fatty liver disease.
Although embodiments of the present invention have been disclosed above, it is not limited to the use of the description and embodiments, it is well suited to various fields of use for the invention, and further modifications may be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the particular details without departing from the general concepts defined in the claims and the equivalents thereof.
Claims (4)
- Use of aldh2 protein in the manufacture of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease.
- 2. Use of a ALDH2 protein according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease, characterized in that: the ALDH2 is specifically activated by alda-1 to prevent and treat the non-alcoholic fatty liver disease induced by MCD.
- 3. Use of a ALDH2 protein according to claim 2 in the manufacture of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease, characterized in that: the specific agonist alda-1 of ALDH2 is prepared into injection in the form of pharmaceutically acceptable excipient/carrier, and is subjected to intermittent subcutaneous injection to excite the activity of ALDH 2.
- 4. Use of a ALDH2 protein according to any one of claims 1 to 3 in the manufacture of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease, characterized in that: the nonalcoholic fatty liver disease is nonalcoholic fatty liver.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310100494.XA CN116098988A (en) | 2023-02-12 | 2023-02-12 | Application of ALDH2 protein in medicine for preventing and/or treating non-alcoholic fatty liver disease |
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