KR20220005948A - Composition for preventing or treating fatty liver disease comprising kynurenic acid - Google Patents
Composition for preventing or treating fatty liver disease comprising kynurenic acid Download PDFInfo
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- KR20220005948A KR20220005948A KR1020200083760A KR20200083760A KR20220005948A KR 20220005948 A KR20220005948 A KR 20220005948A KR 1020200083760 A KR1020200083760 A KR 1020200083760A KR 20200083760 A KR20200083760 A KR 20200083760A KR 20220005948 A KR20220005948 A KR 20220005948A
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- Prior art keywords
- acid
- fatty liver
- liver disease
- kinurenic
- composition
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- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 title claims abstract description 140
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Abstract
Description
본 발명은 키누렌산을 포함하는 지방간 질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating fatty liver disease comprising kinurenic acid.
지방간 질환(fatty liver disease)이란, 지방간이라고도 불리며 간세포에 지방(트리글리세리드 등)이 이상 축적되는 것에 기인하여 간장애를 초래하는 질환이다. 지방간 질환의 초기 병태는 간세포에 지방 침착만을 인정하는 단순성 지방간이며, 그 후에 지방간염(간섬유증을 포함), 또한 간경변이나 간세포암으로 병태가 진행되는 것으로 알려져 있다. 일반적으로, 간장에 지방이 침착되는 원인으로서는, 알콜 섭취, 비만, 당뇨병, 지질대사 이상, 약제(스테로이드, 테트라사이클린 등), Cushing 증후군, 중독(황린 등), 고도의 영양 장애 등을 들 수 있다.Fatty liver disease, also called fatty liver, is a disease that causes liver failure due to abnormal accumulation of fat (triglycerides, etc.) in liver cells. It is known that the initial condition of fatty liver disease is simple fatty liver in which only fat deposition is recognized in hepatocytes, and then the condition progresses to steatohepatitis (including liver fibrosis), and cirrhosis or hepatocellular carcinoma. In general, causes of fat deposition in the liver include alcohol intake, obesity, diabetes, abnormal lipid metabolism, drugs (steroids, tetracycline, etc.), Cushing's syndrome, poisoning (eg yellow phosphorus), and severe nutritional disorders. .
지방간 질환의 원인은 크게 알콜성과 비알콜성으로 나누어지며, 전자를 원인으로 하는 간 질환을 알콜성 지방간질환(알콜성 간장해라고도 불린다), 후자를 원인으로 하는 간 질환을 비알콜성 지방간질환(nonalcoholic fatty liver disease: NAFLD)이라고 부른다. The causes of fatty liver disease are largely divided into alcoholic and non-alcoholic. Alcoholic fatty liver disease (also called alcoholic liver injury) is the liver disease caused by the former, and nonalcoholic fatty liver disease (NFA) is the liver disease caused by the latter. It is called nonalcoholic fatty liver disease (NAFLD).
알콜성 지방간 질환은, 초기의 단순성 지방간으로부터 진행성으로 지방간염, 간경변으로 이행한다. 비알콜성 지방간 질환은, 단순성 지방간에 머물며 병태는 진행되지 않는 것으로 생각되고 있었지만, 최근, 비알콜성 지방성 간질환에 있어서도 단순성 지방간으로부터 지방간염이나 간경변으로 병태가 진행되는 경우가 있는 것으로 밝혀졌다.Alcoholic fatty liver disease progresses from simple fatty liver in the early stage to steatohepatitis and cirrhosis. It was thought that nonalcoholic fatty liver disease remains in simple fatty liver and the condition does not progress, but it has recently been found that the condition may progress from simple fatty liver to steatohepatitis or cirrhosis also in nonalcoholic fatty liver disease.
비알콜성 지방간 질환이란, 간에 유해할 정도로 인정되는 알콜 섭취 병력이 없음에도 불구하고 간 조직 검사에서 알콜성 간염의 특징적인 소견인 지방성 변화(fatty change, steatosis)와 소엽성간염(lobular hepatitis,steatohepatitis)등을 나타내는 경우를 말한다. 간의 병리소견은 단순 지방간(Non-Alcoholic Fatty Liver,NAFL)으로부터 지방간염(Non-Alcoholic Steatohepatits, NASH), 지방간염과 동반된 섬유화증, 간경변증 등의 다양한 스펙트럼을 나타내는데, 비알콜성 지방간질환은 이 모두를 포함하는 의미로 사용된다.Nonalcoholic fatty liver disease refers to fatty change (steatosis) and lobular hepatitis (steatohepatitis), characteristic findings of alcoholic hepatitis in liver biopsy, despite no history of alcohol intake recognized as harmful to the liver. ), and so forth. The pathological findings of the liver show a variety of spectrum from simple fatty liver (Non-Alcoholic Fatty Liver, NAFL) to non-alcoholic Steatohepatits (NASH), fibrosis accompanied by fatty hepatitis, and cirrhosis. It is used in an all-inclusive sense.
이러한 비알콜성 지방간 질환에서는 대부분 인슐린 저항성, 비만, 당뇨병 및 고지혈증을 동반하고 있다. 이러한 합병증이 존재하는 경우에는, 우선 그 치료를 실시하는 것이 필요하다. 비알콜성 지방간질환에 대한 치료의 원칙은, 식사 요법이나 운동요법 등의 생활 습관의 개선이지만, 확실하게 실행하는 것은 어려운 것이 현실이다. Most of these nonalcoholic fatty liver diseases are accompanied by insulin resistance, obesity, diabetes, and hyperlipidemia. When such complications exist, it is necessary to first treat them. Although the principle of treatment for nonalcoholic fatty liver disease is improvement of lifestyle such as diet and exercise therapy, it is difficult to implement it reliably.
비알콜성 지방간염에 있어서는, 간경변간세포암으로 진전될 가능성이 높은 점에서, 보다 적극적인 약물 치료가 필요하다. 비알콜성 지방간염의 병태 발증진행에 중요하다고 생각되고 있는 산화 스트레스나 인슐린 저항성 등의 개선을 목표로 한 치료도 시도되고 있지만, 충분한 과학적 근거가 확립된 치료법이 없는 것이 현실이다In nonalcoholic steatohepatitis, a more aggressive drug treatment is required since it is highly likely to progress to cirrhosis of the liver. Treatments aimed at improving oxidative stress and insulin resistance, which are thought to be important in the pathological development of nonalcoholic steatohepatitis, have been attempted, but the reality is that there is no treatment for which sufficient scientific evidence has been established.
비알코올성 지방간 치료제로서 화학성분을 기반으로 한 외인성 약물이 사용되고 있으나 고용량에서는 간독성을 유발하는 문제점이 있었다. 따라서 독성 및 부작용이 낮은 비알코올성 지방간 치료제가 필요한 실정이다.As a treatment for nonalcoholic fatty liver, exogenous drugs based on chemical components have been used, but there is a problem of inducing hepatotoxicity at high doses. Therefore, there is a need for a therapeutic agent for non-alcoholic fatty liver with low toxicity and side effects.
일 구체예에 따르면 간의 지방 축적 및 지질 생합성을 저해함으로써 지방간 질환을 예방 또는 치료할 수 있는 키누렌산 함유 약학적 조성물을 제공한다. According to one embodiment, there is provided a kinurenic acid-containing pharmaceutical composition capable of preventing or treating fatty liver disease by inhibiting fat accumulation and lipid biosynthesis in the liver.
일 구체예에 따르면 간의 지방 축적 및 지질 생합성을 저해함으로써 지방간 질환을 예방 또는 개선할 수 있는 키누렌산 함유 건강기능식품을 제공한다.According to one embodiment, there is provided a quinurenic acid-containing health functional food capable of preventing or improving fatty liver disease by inhibiting fat accumulation and lipid biosynthesis in the liver.
일 양상은 키누렌산을 포함하는 지방간 질환의 치료 또는 예방용 약학적 조성물을 제공한다. One aspect provides a pharmaceutical composition for the treatment or prevention of fatty liver disease comprising kinurenic acid.
상기 키누렌산(kynurenic acid)은 아미노산 L-트립토판의 대사산물로서 내인성 대사물질이므로 독성 및 부작용의 염려가 낮다. 키누렌산은 신경생리학적 활성이 일부 알려져 있으나 지방간 질환에 대한 효과는 알려진 바가 없다. 본 발명자는 키누렌산을 1차 배양 간세포 및 3T3-L1 지방 세포에 투여한 결과 간세포 특이적으로 지방 축적을 억제할 수 있음을 확인하였다. Since the kynurenic acid is an endogenous metabolite as a metabolite of the amino acid L-tryptophan, there is low concern about toxicity and side effects. Although some known neurophysiological activity of kinurenic acid, its effect on fatty liver disease is unknown. The present inventors confirmed that hepatocyte-specific fat accumulation could be inhibited as a result of administering kinurenic acid to primary cultured hepatocytes and 3T3-L1 adipocytes.
상기 지방간 질환은 알코올성 지방간 질환 또는 비알코올성 지방간 질환일 수 있다. 상기 비알콜성 지방간 질환은 예를 들면 비알콜성 단순성 지방간, 비알콜성 지방간염, 또는 비알콜성 간경변일 수 있다. The fatty liver disease may be alcoholic fatty liver disease or non-alcoholic fatty liver disease. The nonalcoholic fatty liver disease may be, for example, nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, or nonalcoholic cirrhosis.
일 실시예에 따르면, 상기 키누렌산은 간에서의 AMPK를 활성화함으로써 간에서의 중성 지방 축적 및 지질 생합성을 억제할 수 있으므로 지방간 질환의 예방 또는 치료에 사용될 수 있다. According to one embodiment, the kinurenic acid can inhibit triglyceride accumulation and lipid biosynthesis in the liver by activating AMPK in the liver, and thus can be used for preventing or treating fatty liver disease.
상기 약학적 조성물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다. The pharmaceutical composition may be administered in various oral and parenteral formulations during clinical administration, and when formulated, commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. can be manufactured.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 혼합하여 조제될 수 있다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, etc., and such solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose, lactose ( lactose) or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
상기 약학적 조성물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.The effective dosage for the human body of the pharmaceutical composition may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and at regular time intervals according to the judgment of the doctor or pharmacist, once a day to It may be administered in several divided doses.
상기 조성물은 유효성분으로서 키누렌산 외에 공지된 비알콜성 지방간 질환 치료제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다.The composition may further include a known therapeutic agent for non-alcoholic fatty liver disease in addition to kinurenic acid as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases.
다른 양상은 키누렌산을 포함하는 지방간 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다. Another aspect provides a health functional food composition for preventing or improving fatty liver disease comprising kinuronic acid.
상기 키누렌산 및 지방간 질환에 대한 설명은 상술한 바와 동일하다. The description of the kinurenic acid and fatty liver disease is the same as described above.
상기 건강식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 상기 건강기능식품 조성물의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 및 건강식품 조성물 중의 상기 조성물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 유지를 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다. The health food composition may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the health functional food composition may be suitably determined according to the purpose of its use (for prevention or improvement). In general, the amount of the composition in the health functional food and health food composition may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for health maintenance or health control, the amount may be less than or equal to the above range.
상기 건강기능식품에 포함될 수 있는 다른 성분에는 특별한 제한이 없으며 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능식품 및 건강 식품 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.Other ingredients that may be included in the health functional food are not particularly limited and may contain various flavoring agents or natural carbohydrates as additional ingredients. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 health functional food and health food composition of the present invention.
상기 건강식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. The health food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and salts thereof, Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like may be contained.
일 구체예에 따른 키누렌산을 포함하는 조성물을 이용하면, 간에서의 지방 축적 및 지질 생합성을 억제함으로써 지방간 질환을 효과적으로 예방 또는 치료할 수 있다. By using the composition comprising kinurenic acid according to one embodiment, it is possible to effectively prevent or treat fatty liver disease by inhibiting fat accumulation and lipid biosynthesis in the liver.
일 구체예에 따른 키누렌산을 포함하는 조성물을 이용하면, 간세포 특이적으로 지방축적을 억제하므로 부작용이 감소될 수 있다.When the composition comprising kinurenic acid according to one embodiment is used, hepatocyte-specific fat accumulation is inhibited, so that side effects can be reduced.
도 1은 마우스의 1차 배양 간세포에서 팔미틱산에 의한 중성지방의 축적을 키누렌산이 억제한 결과를 확인한 것이다.
도 2는 마우스의 1차 배양 간세포에서 팔미틱산에 의한 processed SREBP1 및 SCD1의 발현 증가를 키누렌산이 억제한 결과를 확인한 것이다.
도 3은 마우스의 1차 배양 간세포에 키누렌산을 처리하고 AMPK의 인산화 증감을 확인한 결과이다.
도 4는 마우스의 1차 배양 간세포에서 팔미틱산에 의한 중성지방 축적이 AMPK 활성화와 연관되어 있음을 확인한 결과이다.
도 5는 마우스의 1차 배양 간세포에 대한 것으로, 키누렌산과 AMPK siRNA를 각각 투여하거나, 또는 모두 투여한 군에서의 processed SREBP1, SCD1 발현량을 측정한 결과이다.
도 6은 고지방식을 급여한 7주된 C57BL/6J(B6) 마우스에서 키누렌산이 미치는 영향을 확인한 결과이다.
도 7은 상기 도 6의 동물모델에서 지질 생합성 유전자인 processed SREBP1 발현량을 측정한 것이다.
도 8은 3T3-L1 지방세포에 대해 팔미틱산과 키누렌산을 처리한 결과를 나타낸 것이다. 1 is a view confirming the result of kinurenic acid inhibiting the accumulation of triglycerides by palmitic acid in primary cultured hepatocytes of mice.
Figure 2 confirms the result of kinuronic acid inhibiting the expression increase of processed SREBP1 and SCD1 by palmitic acid in primary cultured hepatocytes of mice.
Figure 3 is the result of confirming the phosphorylation increase or decrease of AMPK by treating the primary cultured stem cells of mice with kinurenic acid.
4 is a result confirming that triglyceride accumulation by palmitic acid is associated with AMPK activation in primary cultured hepatocytes of mice.
5 is a result of measuring the expression levels of processed SREBP1 and SCD1 in the group to which kinurenic acid and AMPK siRNA were administered, or both, for primary cultured hepatocytes of mice.
Figure 6 is a result confirming the effect of kinuronic acid in 7-week-old C57BL/6J (B6) mice fed a high-fat diet.
7 is a measurement of the expression level of processed SREBP1, which is a lipid biosynthesis gene, in the animal model of FIG. 6 .
8 shows the results of treatment with palmitic acid and kinurenic acid for 3T3-L1 adipocytes.
이하 하나 이상의 구체예를 실시예를 통해 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, one or more specific embodiments will be described in more detail through examples. However, these examples are for illustrative purposes of one or more embodiments, and the scope of the present invention is not limited to these examples.
실험방법Experimental method
1. 키누렌산(Kynurenic acid, KA) 준비1. Preparation of kynurenic acid (KA)
키누렌산(Santa Cruz Biotechnology, Santa Cruz, CA, USA) 용액은 PBS 또는 배지에 100 mM(1000 X stock solution)로 용해시켜 준비하였다. Kinurenic acid (Santa Cruz Biotechnology, Santa Cruz, CA, USA) solution was prepared by dissolving 100 mM (1000 X stock solution) in PBS or medium.
팔미틱산 염(Palmitic acid, Sigma)-BSA 용액은 BSA(지방산 유리 등급; Sigma)를 2%(v/v) 함유한 간세포 유지 배지(hepatocyte maintenance medium)에 혼합하여 팔미틱산(200 uM)을 혼합하여 준비하였다.Palmitic acid salt (Palmitic acid, Sigma)-BSA solution is mixed with BSA (fatty acid free grade; Sigma) in hepatocyte maintenance medium containing 2% (v / v) palmitic acid (200 uM) and prepared.
2. 1차 배양 간세포 준비 및 키누렌산 처리에 의한 AMPK, SREBP1, SCD1 발현량 변화 확인2. Confirmation of AMPK, SREBP1, SCD1 expression level change by primary cultured hepatocyte preparation and kinurenic acid treatment
마우스의 1차 간세포 (Zen-Bio, Research Triangle Park, NC, USA)를 10% 태아 소 혈청(FBS, fetal bovine serum, Invitrogen), 100units/mL 페니실린 및 100 ㎍/ml 스트렙토마이신(Invitrogen)을 포함한 간세포 부착 배지(hepatocyte attachment medium, Zen-Bio)에 배양하였다. 세포가 안착된 후 간세포 유지 배지(hepatocyte maintenance medium, Zen-Bio) 배지에서 옮겨 37℃, 5% CO2 조건에서 배양하였다. 간세포 유지 배지에서 배양한 간세포에서는 마이코플라즈마균(Mycoplasma)이 검출되지 않았다. Mouse primary hepatocytes (Zen-Bio, Research Triangle Park, NC, USA) were treated with 10% fetal bovine serum (FBS, Invitrogen), 100 units/mL penicillin and 100 µg/mL streptomycin (Invitrogen). It was cultured in hepatocyte attachment medium (Zen-Bio). After the cells were settled, they were transferred to a hepatocyte maintenance medium (Zen-Bio) medium and cultured at 37°C and 5% CO2 conditions. Mycoplasma was not detected in the hepatocytes cultured in the hepatocyte maintenance medium.
간세포 유지 배지에서 배양한 간세포에 팔미틱산 염-BSA 및/또는 키누렌산을 24시간 동안 접촉시켰다. 대조군은 2% BSA만을 처리한 군을 사용하였다. Hepatocytes cultured in hepatocyte maintenance medium were contacted with palmitic acid salt-BSA and/or kinuronic acid for 24 hours. As a control group, a group treated with only 2% BSA was used.
3. 웨스턴 블로팅3. Western Blotting
키누렌산과 접촉하여 배양한 간세포를 수득하고, 수득한 간세포를 용해완충액 (PRO-PREP; Intron Biotechnology, Seoul Korea)으로 4℃에서 60분 동안 처리하여 단백질 성분을 추출하였다. Hepatocytes cultured in contact with kinurenic acid were obtained, and the obtained stem cells were treated with a lysis buffer (PRO-PREP; Intron Biotechnology, Seoul Korea) at 4° C. for 60 minutes to extract protein components.
추출한 단백질 시료(35㎍)를 12% SDS-PAGE에 전기영동하여 니트로셀룰로오스막 (Amersham Bioscience, Westborough, MA, USA)에 옮기고, 1차 항체로 검출한 후, 2차 항체와 홀스래디쉬 퍼옥시다제 (Santa Cruz Biotechnology)를 접합시킨 2차 항체로 탐침하였다. 샘플은 ECL키트로 검출되었다.The extracted protein sample (35㎍) was electrophoresed on 12% SDS-PAGE, transferred to a nitrocellulose membrane (Amersham Bioscience, Westborough, MA, USA), and after detection with a primary antibody, secondary antibody and horseradish peroxygen Multi-agent (Santa Cruz Biotechnology) was probed with a conjugated secondary antibody. Samples were detected with the ECL kit.
항-AMPK (1:2500) 및 항-phospho AMPK (1:1000)는 Cell Signaling (Beverly, MA, USA)에서 구입하였다. 항-SREBP1(1:2500), 항-SCD1(1:2500) 및 항-베타액틴(1:5000)은 Santa Cruz Biotechnology에서 구입하였다.Anti-AMPK (1:2500) and anti-phospho AMPK (1:1000) were purchased from Cell Signaling (Beverly, MA, USA). Anti-SREBP1 (1:2500), anti-SCD1 (1:2500) and anti-betaactin (1:5000) were purchased from Santa Cruz Biotechnology.
4. 동물실험4. Animal testing
본 동물 실험은 기관 동물 검토위원회 (중앙 대학교 기관 동물 보호 및 이용위원회, 서울, 대한민국)의 승인을 받아 진행되었다. 동물 실험은 실험실 동물의 관리와 사용을 위한 가이드 (NIH publication, 8th edition, 2011)에 따라 수행되었다. This animal experiment was conducted with the approval of the Institutional Animal Review Committee (Institutional Animal Protection and Use Committee, Chung-Ang University, Seoul, Korea). Animal experiments were performed according to the Guide for the Care and Use of Laboratory Animals (NIH publication, 8th edition, 2011).
7주된 수컷 C57BL/6J(B6) 마우스를 대조군과 실험군으로 나누고, 대조군에는 정상식이(ND, Brogaarden, Gentofte, Denmark)를 8주간 투여하고(이하 정상식이군), 실험군에는 HFD (고지방식이, High Fat Diet, Research Diets, New Brunswick, NJ, USA)를 8주간 투여하였다(이하 고지방식이군). Seven-week-old male C57BL/6J (B6) mice were divided into control and experimental groups, and normal diet (ND, Brogaarden, Gentofte, Denmark) was administered to the control group for 8 weeks (hereinafter referred to as normal diet group), and HFD (high-fat diet, High-fat diet) was administered to the experimental group. Fat Diet, Research Diets, New Brunswick, NJ, USA) was administered for 8 weeks (hereafter, high-fat diet group).
실험군에서 키누렌산 투여군은 HFD 투여기간 동안 키누렌산을 2㎍/mice/2 days의 농도로 꼬리혈관으로 투여하였다(HFD+KA 실험군). In the experimental group, the kinurenic acid administration group was administered kinurenic acid at a concentration of 2㎍/mice/2 days through the tail vein during the HFD administration period (HFD+KA experimental group).
다른 실험군에서 키누렌산 및 AMPK siRNA 투여군은 키누렌산을 상기 HFD+KA 실험군과 동일하게 투여하고, siRNA를 하기 실시예 5-2의 방법으로 투여하였다(HFD+KA+AMPK siRNA 실험군). In the other experimental group, kinurenic acid and AMPK siRNA administration group were administered with kinurenic acid in the same manner as in the HFD+KA experimental group, and siRNA was administered in the manner of Example 5-2 below (HFD+KA+AMPK siRNA experimental group).
실험군 중 일부는 키누렌산 및 AMPK siRNA 대신 PBS를 주입하여 결과를 비교하였다(HFD 실험군). Some of the experimental groups compared the results by injecting PBS instead of kinurenic acid and AMPK siRNA (HFD experimental group).
5. AMPK 발현 억제 확인5. Confirmation of inhibition of AMPK expression
5-1. In vitro 실험5-1. In vitro experiments
간세포 충만도가 약 75% 정도가 되었을 때 FBS가 없는 배지에서 6시간을 적응시킨 후, lipofectamine 2000 (Invitrogen)을 사용하여 AMPK siRNA (Santa Cruz Biotechnology)로 형질전환 (transfection)을 수행하였다. After acclimatization for 6 hours in FBS-free medium when hepatocytes reached about 75% fullness, lipofectamine 2000 (Invitrogen) was used to perform transformation with AMPK siRNA (Santa Cruz Biotechnology).
5-2. In vivo 실험5-2. In vivo experiments
7 주령 B6 마우스를 준비하고, In vivo jetPEI (Polyplus-transfection)와 AMPK siRNA의 혼합액을 2 ug/kg 농도로 마우스의 꼬리 혈관에 2일에 한번씩 8주간 주입하였다.A 7-week-old B6 mouse was prepared, and a mixture of in vivo jetPEI (Polyplus-transfection) and AMPK siRNA was injected into the tail vein of the mouse at a concentration of 2 ug/kg once every 2 days for 8 weeks.
6. 3T3-L1 지방 세포에 대한 키누렌산의 중성지방 축적 억제 효과 확인6. Confirmation of the inhibitory effect of kinurenic acid on triglyceride accumulation on 3T3-L1 adipocytes
3T3-L1 지방 세포를 오일 레드 오(Oil Red-O, sigma)로 염색하여 세포 중성지방(TG)의 축적을 측정하였다. 먼저 3T3-L1 지방 세포를 10% 포르말린으로 40분 동안 처리하여 고정시킨 후, Oil-Red-O 용액으로 37℃에서 1시간 동안 처리하여 중성지방을 염색하였다. Oil-Red-O 용액으로 염색된 3T3-L1 지방 세포에 이소프로판올을 첨가하여 8분간 25℃에서 부드럽게 교반하여 염료를 추출하고, 추출물을 100㎕ 분리하여 분광광도계로 510nm에서의 흡광도를 측정하였다.3T3-L1 adipocytes were stained with Oil Red-O (sigma) to measure the accumulation of cellular triglycerides (TG). First, 3T3-L1 adipocytes were treated with 10% formalin for 40 minutes and fixed, and then treated with Oil-Red-O solution at 37° C. for 1 hour to stain triglycerides. Isopropanol was added to 3T3-L1 adipocytes stained with Oil-Red-O solution, and the dye was extracted by gently stirring at 25°C for 8 minutes.
실시예 1: 간세포에서 키누렌산의 중성지방 축적 억제 확인Example 1: Confirmation of inhibition of triglyceride accumulation of kinurenic acid in hepatocytes
도 1은 마우스의 1차 배양 간세포에서 팔미틱산에 의한 중성지방의 축적을 키누렌산이 억제한 결과를 확인한 것이다. 1 is a view confirming the result of kinurenic acid inhibiting the accumulation of triglycerides caused by palmitic acid in primary cultured hepatocytes of mice.
도 1에 따르면, 팔미틱산을 처리한 군은 축적된 중성지방이 증가하였으나, 키누렌산을 함께 처리한 군에서는 팔미틱산에 의한 중성지방 축적이 농도의존적으로 억제되었다. 실험 결과에 따르면 키누렌산은 간에서의 지방 축적을 억제할 수 있을 것으로 예상된다. According to FIG. 1, the group treated with palmitic acid increased the accumulated triglycerides, but in the group treated with kinurenic acid, the accumulation of triglycerides by palmitic acid was inhibited in a concentration-dependent manner. According to the experimental results, it is expected that kinurenic acid can inhibit fat accumulation in the liver.
실시예 2: 간세포에서 키누렌산에 의한 지질 생합성 유전자 발현억제 확인Example 2: Confirmation of inhibition of lipid biosynthesis gene expression by kinurenic acid in hepatocytes
도 2는 마우스의 1차 배양 간세포에서 팔미틱산에 의한 processed SREBP1 및 SCD1의 발현 증가를 키누렌산이 억제한 결과를 확인한 것이다. 상기 processed SREBP1 및 SCD1은 지질 생합성에 관여하는 유전자이다. Figure 2 confirms the result of kinurenic acid inhibiting the expression increase of processed SREBP1 and SCD1 by palmitic acid in primary cultured hepatocytes of mice. The processed SREBP1 and SCD1 are genes involved in lipid biosynthesis.
도 2에 따르면, 팔미틱산을 처리한 군은 processed SREBP1 및 SCD1의 발현이 증가하였으나, 키누렌산을 함께 처리한 군은 팔미틱산에 의한 processed SREBP1 및 SCD1의 발현 증가가 농도의존적으로 억제되었다. 실험 결과에 따르면 키누렌산은 간에서의 지질 생합성을 억제할 것으로 예상된다. According to FIG. 2, the group treated with palmitic acid increased the expression of processed SREBP1 and SCD1, but in the group treated with kinurenic acid, the increase in the expression of processed SREBP1 and SCD1 by palmitic acid was inhibited in a concentration-dependent manner. According to the experimental results, kinurenic acid is expected to inhibit lipid biosynthesis in the liver.
실시예 3: 간세포에서 키누렌산에 의한 AMPK의 인산화 증가Example 3: Increased phosphorylation of AMPK by kinurenic acid in hepatocytes
도 3은 마우스의 1차 배양 간세포에 키누렌산을 처리하고 AMPK의 인산화 증감을 확인한 결과이다. 간에서 AMPK(AMP-activated protein kinase)가 인산화됨으로서 활성화되면 지방산과 콜레스테롤의 합성을 억제하고 지방산의 산화를 촉진한다. Figure 3 is the result of confirming the phosphorylation increase or decrease of AMPK by treating the primary cultured stem cells of mice with kinurenic acid. When activated by phosphorylation of AMPK (AMP-activated protein kinase) in the liver, it inhibits the synthesis of fatty acids and cholesterol and promotes the oxidation of fatty acids.
도 3에 따르면 키누렌산을 처리한 군은 AMPK의 인산화가 농도의존적으로 증가하였다. 실험 결과에 따르면 키누렌산은 간에서 AMPK 활성화를 촉진하여 지방산의 합성을 억제하고 지방산의 산화를 촉진할 것으로 예상된다. According to FIG. 3, the phosphorylation of AMPK was increased in a concentration-dependent manner in the group treated with kinurenic acid. According to the experimental results, quinurenic acid is expected to inhibit fatty acid synthesis and promote fatty acid oxidation by promoting AMPK activation in the liver.
실시예 4: 키누렌산의 지방간 억제 기전 확인Example 4: Confirmation of the mechanism of inhibition of fatty liver of kinurenic acid
도 4는 마우스의 1차 배양 간세포에서 팔미틱산에 의한 중성지방 축적이 AMPK 활성화와 연관되어 있음을 확인한 결과이다. 4 is a result confirming that triglyceride accumulation by palmitic acid is associated with AMPK activation in primary cultured hepatocytes of mice.
도 4에 따르면, 팔미틱산과 키누렌산을 모두 처리한 군에서는 지방 축적이 억제되었으나, 팔미틱산, 키누렌산, 및 AMPK siRNA를 모두 처리한 군에서는 지방 축적이 증가하였다. 이는 키누렌산에 의해 활성화된 AMPK가 siRNA에 의해 다시 비활성화됨으로서 지방 축적이 증가하였음을 시사한다. 따라서 키누렌산은 간에서의 AMPK 활성화를 촉진하여 지방 축적을 억제함을 알 수 있다. According to FIG. 4 , fat accumulation was inhibited in the group treated with both palmitic acid and kinurenic acid, but fat accumulation was increased in the group treated with palmitic acid, kinurenic acid, and AMPK siRNA. This suggests that fat accumulation was increased as AMPK activated by kinurenic acid was again inactivated by siRNA. Therefore, it can be seen that kinurenic acid inhibits fat accumulation by promoting AMPK activation in the liver.
도 5는 마우스의 1차 배양 간세포에 대한 것으로, 키누렌산과 AMPK siRNA를 각각 투여하거나, 또는 모두 투여한 군에서의 processed SREBP1, SCD1 발현량을 측정한 결과이다. 5 is a result of measuring the expression levels of processed SREBP1 and SCD1 in the group to which kinurenic acid and AMPK siRNA were administered, or both, for primary cultured hepatocytes of mice.
도 5에 따르면, 키누렌산만을 투여한 군에서는 processed SREBP1 및 SCD1의 발현량이 감소하였으나, 키누렌산과 AMPK siRNA를 함께 투여한 군에서는 processed SREBP1 및 SCD1의 발현량이 다시 증가하였다. 이는 키누렌산에 의해 억제된 지질 생합성 유전자가 AMPK 억제에 의해 다시 활성화되었음을 시사한다. 따라서 키누렌산은 간에서의 AMPK를 활성화시킴으로서 지질 생합성을 억제함을 알 수 있다.According to FIG. 5 , the expression levels of processed SREBP1 and SCD1 decreased in the group administered with only kinurenic acid, but the expression levels of processed SREBP1 and SCD1 increased again in the group administered with kinurenic acid and AMPK siRNA. This suggests that the lipid biosynthesis gene suppressed by kinurenic acid was reactivated by AMPK inhibition. Therefore, it can be seen that kinurenic acid inhibits lipid biosynthesis by activating AMPK in the liver.
종합하면, 키누렌산은 간에서 AMPK를 활성화시킴으로서 지방축적을 억제하고 지질 생합성을 저해함을 알 수 있다. Taken together, it can be seen that kinurenic acid inhibits fat accumulation and lipid biosynthesis by activating AMPK in the liver.
실시예 5: 동물 모델에서의 지방 축적 및 지질 생합성 억제 확인Example 5: Confirmation of inhibition of fat accumulation and lipid biosynthesis in animal models
도 6은 고지방식을 급여한 7주된 C57BL/6J(B6) 마우스에서 키누렌산이 미치는 영향을 확인한 결과이다. 도 6에 따르면 고지방식(HFD)를 급여한 군은 레드오에 의해 염색된 중성지방의 양이 크게 증가하였다. 그러나 키누렌산을 투여한 군은 고지방식에도 불구하고 중성지방의 양이 크게 증가하지 않았다. 반면, 키누렌산과 AMPK siRNA을 함께 투여한 군에서는 중성지방의 양이 다시 증가하였다. 상기 동물 모델 실험 결과에 따르면 키누렌산은 간에서의 AMPK 활성화를 촉진하여 간에서의 지방 축적을 억제함을 알 수 있었다. Figure 6 is a result confirming the effect of kinuronic acid in 7-week-old C57BL/6J (B6) mice fed a high-fat diet. According to FIG. 6 , the group fed with a high-fat diet (HFD) significantly increased the amount of triglycerides stained by Red O. However, the amount of triglycerides did not significantly increase in the group administered with kinurenic acid despite the high-fat diet. On the other hand, the amount of triglycerides increased again in the group administered with kinurenic acid and AMPK siRNA. According to the results of the animal model experiment, it was found that kinurenic acid inhibits fat accumulation in the liver by promoting AMPK activation in the liver.
도 7은 상기 도 6의 동물모델에서 지질 생합성 유전자인 processed SREBP1 발현량을 측정한 것이다. 도 7에 따르면 키누렌산은 간에서 AMPK 활성화를 촉진함으로써 지질 생합성 유전자의 발현을 억제함을 알 수 있었다. 7 is a measurement of the expression level of processed SREBP1, which is a lipid biosynthesis gene, in the animal model of FIG. 6 . According to FIG. 7, it was found that kinurenic acid suppressed the expression of lipid biosynthesis genes by promoting AMPK activation in the liver.
실시예 6: 키누렌산의 간세포 특이적 지방 축적 억제 확인 Example 6: Confirmation of inhibition of hepatocyte-specific fat accumulation by kinurenic acid
도 8은 3T3-L1 지방세포에 대해 팔미틱산과 키누렌산을 처리한 결과를 나타낸 것이다. 도 8에 따르면 3T3-L1 지방세포에 팔미틱산을 처리하고, 키누렌산을 0 μM, 30 μM, 100 μM 추가로 처리하였으나 중성지방의 축적이 억제되지 않았다. 이는 키누렌산의 지방 축적 및 지질 생합성 억제 효과가 간세포에 대해 특이적으로 나타나는 것임을 의미한다. 8 shows the results of treatment with palmitic acid and kinurenic acid for 3T3-L1 adipocytes. According to FIG. 8, 3T3-L1 adipocytes were treated with palmitic acid and additionally treated with 0 μM, 30 μM, and 100 μM of kinurenic acid, but the accumulation of triglycerides was not inhibited. This means that the fat accumulation and lipid biosynthesis inhibitory effects of kinurenic acid appear specifically for hepatocytes.
Claims (6)
A pharmaceutical composition for the treatment or prevention of fatty liver disease comprising kinurenic acid.
상기 키누렌산은 간세포 특이적으로 지방 축적을 억제하는 것인,
지방간 질환 치료 또는 예방용 조성물.
According to claim 1,
The kinurenic acid is to inhibit hepatocyte-specific fat accumulation,
A composition for treating or preventing fatty liver disease.
상기 키누렌산은 간에서의 AMPK를 활성화하는 것인,
지방간 질환의 치료 또는 예방용 조성물.
According to claim 1,
The kinurenic acid will activate AMPK in the liver,
A composition for treating or preventing fatty liver disease.
상기 키누렌산은 간에서의 중성 지방 축적을 억제하는 것인,
지방간 질환의 치료 또는 예방용 조성물.
According to claim 1,
The kinurenic acid is to inhibit the accumulation of triglycerides in the liver,
A composition for treating or preventing fatty liver disease.
상기 키누렌산은 간에서의 지질 생합성을 억제하는 것인,
지방간 질환의 치료 또는 예방용 조성물.
According to claim 1,
The kinurenic acid is to inhibit lipid biosynthesis in the liver,
A composition for treating or preventing fatty liver disease.
A health functional food composition for preventing or improving fatty liver disease containing kinurenic acid.
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| C.Lindquist et al., BBA-Molecular and Cell Biology of Lipids, Vol.1865, Art.158543. (Available online: 30. Oct. 2020.) * |
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