KR20220049790A - Use of 4-hexylresorcinol for treating metabolic diseases and liver diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases and liver diseases comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient. Since it is possible to inhibit the expression of HDAC and promote the activity of SIRT through 4-hexylresorcinol, the present invention can contribute to the prevention, alleviation, or treatment of metabolic diseases and liver diseases caused by changes in the expression or activity of HDAC and SIRT from 4-hexylresorcinol.

Description

Use of 4-hexylresorcinol for treating metabolic diseases and liver diseases

The present invention relates to the use of 4-hexylresorcinol for the treatment of metabolic diseases and liver diseases.

Histones are tightly bound to DNA with genetic information to form nucleosomes in the nucleus, and the post-translational modification of these DNA-binding proteins can regulate gene expression and signal transduction systems. During this transformation process, histone acetylation is largely regulated by two enzymes, histone acetyltransferase (HAT) and histone deacetylase (HDAC), which are transcription factors, signal transduction mediators and The activity of the same non-histone protein can also be modulated. HAT proteins increase the acetylation of hormone receptors, and the acetylated hormone receptors overexpress each target protein, causing increased cancer growth and development. In addition to cancer, hyperacetylation of histones is associated with diseases such as obesity, diabetes, and degenerative brain disease. C/EBP (CCAAT/Enhancer-binding Protein), an obesity-related factor, stimulates and activates PPAR (peroxisome proliferator-activated receptor)-α/γ when hyperacetylation occurs by HAT protein, thereby promoting differentiation and development of adipocytes can be Therefore, it has been reported that suppressing the activity of HAT protein and blocking or inhibiting histone acetylation by HAT protein can inhibit the induction or progression of related diseases.

HDAC activity inhibitors have been researched and developed for the purpose of controlling such acetylation, and HDAC inhibitors studied to date include synthetic peptide-CoA conjugate, isothiazolone, polyprenylated benzophenone. synthetic compounds such as (polyprenylated benzophenone), curcumin, or anacardic acid.

Sirtuin (SIRT) is a NAD (nicotinamide adenine dinucleotide)-dependent histone deacetylase, distributed in the cell nucleus or cytoplasm, and mainly lysine of histone H3 (Lys9 or Lys14) of various transcriptional regulators in the nucleus However, it works by deacetylating lysine (Lys16) of histone H4. Mammalian sirtuins affect the signaling system through deacetylation of transcription factors other than histones. Transcription factors that interact with sirtuins include p53, forkhead transcription factor (FOXO), peroxisome growth factor- Active receptor gamma coactivator 1-alpha (peroxisome proliferator-activated receptor γ coactivator 1-α; PGC1-α) and peroxisome proliferator-activated receptor-gamma (PPAR-γ), etc. There, these factors are known to be related to aging, cell circulation regulation, apoptosis, metabolism, or inflammation.

The present invention aims to establish an active ingredient capable of treating diseases caused by changes in HDAC and SIRT activity by regulating the histone deacetylase (HDAC) and sirtuin (SIRT) activity.

Journal of Cell Science. 2011; 124:833-838

It is an object of the present invention to provide a novel use of 4-hexylresorcinol for preventing, ameliorating or treating metabolic diseases and liver diseases.

The present inventors confirmed that the activity of histone deacetylase (HDAC) is inhibited and the activity of sirtuin (SIRT) is promoted in osteoblasts and endothelial vascular cells treated with 4-hexylresorcinol. The present invention was completed by confirming that 4-hexylresorcinol can be usefully used for the treatment of metabolic diseases and liver diseases caused by promoting the activity of an acetylation enzyme and inhibiting the activity of a sirtuin.

Accordingly, the present invention relates to a novel pharmaceutical use of 4-hexylresorcinol for the treatment of metabolic and liver diseases.

Hereinafter, the configuration of the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating metabolic diseases and liver diseases comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, “4-hexylresorcinol” is a compound having the IUPAC name of 4-hexylbenzene-1,3-diol, and the following formula 1 It is a compound represented by:

[Formula 1]

In the present invention, the 4-hexylresorcinol may be used interchangeably with “4-hexylbenzene-1,3-diol” or “4-HR”.

In the present invention, the pharmaceutically acceptable salt of 4-hexylresorcinol is a concentration having a relatively non-toxic and harmless effective action to the patient, and the side effects caused by the salt are not the beneficial effects of 4-hexylresorcinol. An organic or inorganic addition salt that does not drip. For example, the pharmaceutically acceptable salt may be an acid addition salt formed using an organic or inorganic acid, wherein the organic acid is, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid , maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid, benzene sulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid salts, and inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid salts. Preferably, the pharmaceutically acceptable salt may be in the form of a citrate or hydrochloride salt. In addition, the pharmaceutically acceptable salts may be alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.).

In the present invention, the metabolic disease may be one or more selected from the group consisting of obesity, diabetes, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and metabolic syndrome. The liver disease may be at least one selected from the group consisting of non-alcoholic fatty liver, alcoholic fatty liver, and steatohepatitis.

According to the following examples, 4-hexylresorcinol is treated in osteoblasts and endothelial cells to inhibit the expression of histone deacetylase (HDAC), increase the acetylation of lysine (Lys), and sirtuin Since it can promote the activity of (SIRT), it can be usefully used for the treatment of diseases caused by an increase in the activity of HDAC and a decrease in the activity of SIRT, that is, a metabolic disease and a liver disease.

In the present invention, the 4-hexyl resorcinol (4-HR) may be included in a concentration of 0.1 μM to 1 mM. For example, 4-hexylresorcinol may be included at a concentration of 0.5 μM to 500 μM, or 1 μM to 100 μM. In the concentration range of 4-hexylresorcinol as described above, the effect of inhibiting the activity of histone deacetylase (HDAC) and increasing the activity of sirtuin (SIRT) can be maximized.

The "histone deacetylase (HDAC)" is present in the nucleus, mitochondria, or cytoplasm and plays a role in regulating the expression of specific genes. When the histone deacetylase (HDAC) is overexpressed, it is associated with the occurrence of various diseases, and as such diseases, heart disease, autoimmune disease, musculoskeletal disease, and malignant tumor are known. HDACs are classified into three major groups based on their homology to yeast proteins: type I includes HDAC1, HDAC2, HDAC3 and HDAC8, and type II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10; , type III includes sirtuins in mammals (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7), and type IV includes HDAC11. The type I HDAC is most similar to the yeast transcriptional regulator RPD3, and the type II HDAC is most similar to the yeast HDAC1 enzyme. HDAC1, one of the histone deacetylases, plays a role in regulating the expression of growth factors, and has a characteristic of being overexpressed in modified cells or actively proliferating cells. In the case of HDAC3, it functions in protein acetylation, chromatin remodeling, and gene expression, and is known to be involved in cell proliferation and death. In the case of HDAC4, it is known to directly regulate muscular atrophy, and in the case of HDAC5, it is known to be involved in the development of inflammation or fibrotic disease. In one embodiment, the pharmaceutical composition of the present invention may reduce the expression of HDAC1, HDAC3, HDAC4 and HDAC5.

The “sirtuin (SIRT)” is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, and is distributed in the cell nucleus or cytoplasm, mainly lysine (Lys9 or Lys14) of histone H3 of various transcription factors in the nucleus or It works by deacetylating lysine (Lys16) of histone H4. Mammalian sirtuins affect the signaling system through deacetylation of transcription factors other than histones. Transcription factors that interact with sirtuins include p53, forkhead transcription factor (FOXO), peroxisome growth factor- Active receptor gamma coactivator 1-alpha (peroxisome proliferator-activated receptor γ coactivator 1-α; PGC1-α) and peroxisome proliferator-activated receptor-gamma (PPAR-γ), etc. It is known to be related to aging, cell circulation regulation, apoptosis, metabolism, inflammation, and the like. In one embodiment, the pharmaceutical composition of the present invention may promote the activity of SIRT6.

In addition, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes carriers and vehicles commonly used in the pharmaceutical field, and specifically, ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer substances (eg, , various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (eg protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloids silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substrates, polyethylene glycol, sodium carboxymethylcellulose, polyarylate, wax or wool, and the like.

In addition, the composition of the present invention may further include a lubricant, a wetting agent, an emulsifier, a suspending agent or a preservative, etc. in addition to the above components.

In one embodiment, the composition according to the present invention may be prepared as an aqueous solution for parenteral administration, preferably a buffered solution such as Hank's solution, Ringer's solution or physically buffered saline. can be used Aqueous injection suspensions may contain substrates capable of increasing the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.

The composition of the present invention may be administered systemically or locally, and may be formulated into a formulation suitable for such administration by a known technique. For example, for oral administration, it may be administered by mixing with an inert diluent or an edible carrier, sealing it in a hard or soft gelatin capsule, or pressing it into a tablet. For oral administration, the active compound can be mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.

Various formulations for injection, parenteral administration, etc. can be prepared according to techniques known in the art or commonly used techniques. In addition, an effective amount of 4-hexylresorcinol may be formulated into a solution immediately prior to administration in saline or buffer in a form suitable for intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like, and administered.

In the present invention, the term "administration" means introducing the composition of the present invention to a patient by any suitable method, and the route of administration of the composition of the present invention is through various oral or parenteral routes as long as it can reach the target tissue. may be administered. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration may be administered, but is not limited thereto.

The present invention also provides a method for treating metabolic and liver diseases, comprising administering to a subject in need thereof a therapeutically effective amount of 4-hexylresorcinol.

As used herein, a subject refers to a mammal that is the subject of treatment, observation or experiment, and preferably refers to a human.

In the treatment method, the description of 4-hexylresorcinol, metabolic disease and liver disease may be applied as it is described above.

As used herein, "effective amount" means an amount necessary to delay or completely stop the onset or progression of a specific disease to be treated, and an effective amount of 4-hexylresorcinol included in the pharmaceutical composition of the present invention is metabolically It means an amount required to suppress the activity of histone deacetylase and promote the activity of sirtuin in diseases and liver diseases. Accordingly, the effective amount is the type of disease, the severity of the disease, the type and content of other components contained in the composition, and the age, weight, general health condition, sex and diet of the patient, administration time, administration route, treatment period, concurrent use It can be adjusted depending on various factors including the drug being used. It is apparent to those skilled in the art that a suitable total daily amount can be determined by a treating physician within the scope of sound medical judgment.

For the purposes of the present invention, a specific therapeutically effective amount for a particular patient will depend on the specific composition, age, weight, general health, and sex of the patient, including the type and extent of the response to be achieved and, if desired, whether other agents are used. It is preferable to apply differently depending on various factors including diet, administration time, administration route and secretion rate of the composition, treatment period, drug used together with or concurrently with a specific composition, and similar factors well known in the pharmaceutical field.

As used herein, “treatment” refers to an approach for obtaining beneficial or desirable clinical results. For the purposes of the present invention, beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, reduction of the extent of the disease, stabilization (ie, not worsening) of the disease state, delay or reduction in rate of disease progression, disease state improvement or temporary relief and alleviation (partial or total), detectable or undetectable. "Treatment" can also mean increasing survival as compared to expected survival in the absence of treatment. “Treatment” refers to both therapeutic treatment and prophylactic or prophylactic measures. Such treatments include the treatment required for the disorder being prevented as well as the disorder that has already occurred. To “ameliorate” a disease means that the extent and/or undesirable clinical signs of the disease state are reduced and/or the time course of progression is delayed or lengthened as compared to no treatment do.

Advantages and features of the present invention, and methods for achieving them, will become apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in a variety of different forms, and only these embodiments allow the disclosure of the present invention to be complete, and common knowledge in the technical field to which the present invention belongs It is provided to fully inform the possessor of the scope of the invention, and the present invention is only defined by the scope of the claims.

According to the present invention, since 4-hexylresorcinol can inhibit the expression of HDAC and promote the activity of SIRT from treatment with 4-hexylresorcinol, metabolic diseases caused by changes in expression or activity of HDAC and SIRT and It may contribute to the prevention, alleviation or treatment of liver disease.

1 shows the evaluation results of SIRT activity of Saos-2 cells treated with 1-100 μM of 4-HR.
Figure 2 shows the evaluation results of SIRT activity of HUVEC cells treated with 1-100 μM 4-HR.
3 shows the results of NAD/NADH analysis of Saos-2 cells treated with 1-100 μM of 4-HR.
4 shows the results of NAD/NADH analysis of HUVEC cells treated with 1-100 μM 4-HR.
Figure 5 confirms the change in SIRT expression of Saos-2 cells and HUVEC cells treated with 1-100 μM 4-HR.
6 is a result confirming the change in the HDAC enzyme activity of Saos-2 cells and HUVEC cells treated with 1-100 μM 4-HR.
7 is a result of confirming the expression changes of HDAC1, HDAC3, HDAC4 and HDAC5 in Saos-2 cells treated with 1-100 μM 4-HR.
8 shows the results of confirming the expression changes of HDAC1, HDAC3, HDAC4 and HDAC5 in HUVEC cells treated with 1-100 μM 4-HR.
9 is a result confirming the expression change of HDAC1, HDAC3, HDAC4 and HDAC5 in Saos-2 cells and HUVEC cells treated with 1-100 nM tricostatin A.
10 is a result confirming the expression change of Ac-Lys in HUVEC cells treated with 1-100 μM 4-HR.
11 is a result confirming the expression change of Ac-Lys in Saos-2 cells treated with 1-100 μM 4-HR.
12 is a result confirming the expression change of Ac-Lys in Saos-2 cells and HUVEC cells treated with 1-100 nM tricostatin A.

Hereinafter, the present application will be described in detail through examples. The following examples only illustrate the present application, and the scope of the present application is not limited to the following examples.

[Example]

[Example 1] Saos-2 cell line and HUVEC cell line culture and 4-HR treatment

Saos-2 cell line (Korea Cell Line Bank, No.30085, Seoul, Korea) was mixed with 10% FBS (Euroclone, Milano, Italy), 50 U/mL penicillin G, 50 µg/mL streptomycin sulfate, 2 g/mL. It was suspended in RPMI 1640 medium supplemented with L of sodium carbonate and 0.11 g/L of sodium pyruvate. HUVECs cell line (Lonza, Walkersville, MD, USA) was purchased and then cultured. The medium was cell basal medium with supplement (EGMTM-2, Clonetics®Lonza, Walersville, MD, USA). Cells were cultured at 37.5° C., 5% CO ₂ . Mycoplasma experiments were performed regularly to ensure that only cells without mycoplasma were analyzed. 4-HR and trichostatin-A were purchased from Sigma-Aldrich (St. Louis, MO, USA).

To analyze the protein expression levels of HDAC1, HDAC3, HDAC4, HDAC5 and acetylated lysine, primary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA), Saos-2 cells and HUVECs. Cells were treated with 4-HR at concentrations of 1, 10 and 100 μM. As a control group, only solvent-treated Saos-2 cells and HUVEC cells were used. Proteins were obtained after 2, 8 and 24 hours of 4-HR treatment. The obtained protein was mixed with sodium dodecyl sulfate buffer and denatured by heating. The denatured protein was electrophoresed on a 10% polyacrylamide gel. The gel was transferred to a polyvinylidene difluoride membrane. After blocking, the membrane was detected with primary antibody (dilution ratio = 1:500). Blots were imaged and quantified using a ChemiDoc XRS system (Bio-Rad Laboratories, Hercules, CA, USA). According to the manufacturer's instructions, the IC50 of Tricostatin-A was 20 nM. Therefore, the level of protein expression after 24 hours by administering 1-100 nM of tricostatin-A was investigated.

[Example 2] SIRT activity evaluation

Sirtuin (SIRT) activity evaluation was performed in Saos-2 cells and HUVEC cells with the Universal SIRT Activity Assay Kit (CAT#: ab156915, Abcam, Cambridge, UK). The kit was designed to measure the activity of the SIRT isoform (SIRT 1-7) under each experimental condition. Sirtuins are enzymes belonging to Class III of histone deacetylases and require NAD+ for their activity. Therefore, in the experiment, the cell nuclear fraction was separated from the cells, and then, an assay buffer and a substrate were added and incubated. Then, a capture antibody was administered to the cultured cells, a detection antibody and an enhancer were administered, and then a photosensitizer was administered to develop color. Sirtuin activity was evaluated by measuring absorbance to confirm color development. The results of evaluation of the sirtuin activity of 4-hexylresorcinol on Saos-2 cells and HUVEC cells are shown in FIGS. 1 and 2, respectively.

In the case of Saos-2 cells, as shown in FIG. 1 , as a result of evaluating the activity of SIRT after treatment with 1-100 μM of 4-hexylresorcinol to Saos-2 cells, 4-hexylresorcinol was administered It was confirmed that the activity of sirtuin increased at a high concentration as time passed.

In the case of HUVEC cells, as in Saos-2 cells, it was confirmed that the sirtuin activity increased at a high concentration with the lapse of time after administration of 4-hexylresorcinol.

[Example 3] NAD / NADH analysis

NAD+ and NADH are essential factors for sirtuin activity. NAD+ and NADH were measured using the NAD/NADH assay kit (CAT#: ab65348, Abcam, Cambridge, UK). The experiment was performed according to the manufacturer's instructions, and after taking a sample from the cells, the sample was treated at 60° C. for 30 minutes to measure NADH. It was then stored on ice to lower the temperature. In this case, the process of storing on ice was omitted in the specimen for measuring the ratio. Then, the specimen was transferred to each well, a reaction solution was added thereto, and the reaction solution was allowed to react at room temperature for 5 minutes. After the addition of NADH developer (developer), incubated for 1 to 4 hours during the reaction cycle. Absorbance was measured for 1 to 4 hours using a microplate reader. The results of NAD/NADH analysis of 4-hexylresorcinol on Saos-2 cells and HUVEC cells are shown in FIGS. 3 and 4, respectively.

As shown in FIG. 3 , in the case of Saos-2 cells following 4-HR treatment, it was confirmed that the amount of NADH was slightly increased after 24 hours of treatment with 4-HR at a concentration of 100 μM. . However, with respect to the ratio of NAD/NADH, it was confirmed that the experimental group administered with 4-HR showed a value of about 5 after 24 hours, compared to about 3 in the control group.

In addition, in the case of HUVEC cells (FIG. 4), it was confirmed that the overall amount of NADH was slightly increased according to the administration of 4-HR, and the ratio of NAD/NADH was overall in the experimental group administered with 4-HR compared to the control group. increasing pattern could be seen.

[Example 4] Confirmation of Sirtuin Expression Change

Sirtuin expression changes in Saos-2 cells and HUVEC cells according to 4-HR administration were confirmed. As a result, as shown in FIG. 5 , in the case of SIRT6, it was confirmed that the expression increased according to the administration of 4-HR.

[Example 5] HDAC activity assay

HDAC activity assay kit (CAT#: ab156064, Abcam, Cambridge, UK) was used to quantitatively confirm changes in histone deacetylase (HDAC) activity. The experiment was performed according to the manufacturer's instructions, and the inhibitor (4-HR) was added to the reaction well consisting of the HDAC assay buffer and the substrate and the sample was mixed well. Control HDACs and lysates of prepared cells were then added to each well. Then, after incubation at room temperature for 20 minutes, a stop solution and a developer were added to each well. Then, it was incubated at room temperature for 30 minutes. In the cultured cells, the degree of enzyme activity was quantified by measuring the absorbance at Ex/Em=355/460 nm in an absorbance meter to confirm the degree of fluorescence.

As a result, it was confirmed that administration of 4-HR reduced the HDAC enzyme activity in a concentration- and time-dependent manner in Saos-2 cells and HUVEC cells ( FIG. 6 ). A statistically significant decrease in activity was observed in the range of 10 to 100 μM even when compared with the control group (p<0.05).

[Example 6] Confirmation of HDAC expression change

Expression changes of HDAC1, HDAC3, HDAC4, and HDAC5 according to the treatment of 4-hexylresorcinol in Saos-2 cells and HUVEC cells were confirmed.

First, the expression changes of HDAC1, HDAC3, HDAC4 and HDAC5 according to 4-HR treatment in Saos-2 cells and HUVEC cells were confirmed.

As a result, as shown in FIGS. 7 and 8 , it was confirmed that the expression of HDAC decreased with time after 4-HR treatment in Saos-2 cells, which are osteoblasts, and HUVEC cells, which are vascular endothelial cells. .

Next, the expression changes of HDAC1, HDAC3, HDAC4, and HDAC5 were observed 24 hours after administration of 1 to 100 nM of tricostatin A to Saos-2 cells and HUVEC cells.

As a result, as shown in FIG. 9, it was possible to confirm subtle expression changes of HDAC1, HDAC3, HDAC4, and HDAC5 according to the treatment of tricostatin-A, but the expression increase or decrease was significantly increased compared to the experimental group treated with 4-HR. didn't

Next, a change in the expression of acetylated lysine (Ac-Lys), which is inevitably increased when HDAC is inhibited, was confirmed.

As a result, as shown in FIG. 10 , it was confirmed that the expression of Ac-Lys was increased in HUVEC cells after administration of 4-HR, and as in FIG. 11 , the expression of Ac-Lys was increased in Saos-2 cells as well. results could be confirmed.

In the results of treating Saos-2 cells and HUVEC cells with tricostatin A ( FIG. 12 ), it was observed that the expression of Ac-Lys was increased in the concentration range of 10 to 100 nM after 24 hours.

Therefore, it was confirmed that, through the above results, HDAC expression inhibition and Ac-Lys expression increased in 4-hexylresorcinol (4-HR) as in tricostatin A, a known standard material.

Claims (6)

A pharmaceutical composition for preventing or treating metabolic disease or liver disease, comprising 4-hexylresorcinol or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 1,
4-Hexyl resorcinol is a pharmaceutical composition for preventing or treating metabolic disease or liver disease, which is contained in a concentration of 0.1 μM to 1 mM. The method of claim 1,
4-Hexyl resorcinol is a pharmaceutical composition for the prophylaxis or treatment of metabolic diseases or liver diseases that promotes the activity of sirtuin (silent mating type information regulation 2 homolog; sirtuin). The method of claim 1,
4-Hexyl resorcinol is a pharmaceutical composition for preventing or treating metabolic disease or liver disease by inhibiting the activity of histone deacetylase (HDAC). The method of claim 1,
Metabolic disease is obesity, diabetes, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and metabolic syndrome at least one selected from the group consisting of metabolic disease or a pharmaceutical composition for the prevention or treatment of liver disease. The method of claim 1,
Liver disease is a non-alcoholic fatty liver, alcoholic fatty liver, and a pharmaceutical composition for the prevention or treatment of at least one metabolic disease or liver disease selected from the group consisting of fatty liver.

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