JP2018154569A - Agent for suppressing enlargement of lipid droplets in liver, composition for suppressing enlargement of lipid droplets in liver and food composition for suppressing enlargement of fat droplets in liver - Google Patents
Agent for suppressing enlargement of lipid droplets in liver, composition for suppressing enlargement of lipid droplets in liver and food composition for suppressing enlargement of fat droplets in liver Download PDFInfo
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- JP2018154569A JP2018154569A JP2017050740A JP2017050740A JP2018154569A JP 2018154569 A JP2018154569 A JP 2018154569A JP 2017050740 A JP2017050740 A JP 2017050740A JP 2017050740 A JP2017050740 A JP 2017050740A JP 2018154569 A JP2018154569 A JP 2018154569A
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- Prior art keywords
- liver
- arctigenin
- enlargement
- composition
- lipid droplets
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Abstract
Description
本発明は、肝臓の脂肪滴の肥大化を抑制する作用を有する薬剤、組成物および食品組成物に関する。 The present invention relates to a drug, a composition and a food composition having an action of suppressing enlargement of lipid droplets in the liver.
肝臓は、小腸で吸収された脂質を脂肪酸に分解し、脂肪酸から中性脂肪を合成してエネルギー源として肝細胞中に蓄積する。しかし、エネルギーとして使用されるよりも蓄積される脂肪が多いと、肝細胞に脂肪が溜まってしまう。全肝細胞の30％以上が脂肪化した状態を脂肪肝という。 The liver breaks down lipids absorbed in the small intestine into fatty acids, synthesizes neutral fats from the fatty acids and accumulates them in the hepatocytes as an energy source. However, if more fat is accumulated than is used as energy, fat accumulates in hepatocytes. A state in which 30% or more of all hepatocytes are fattened is called fatty liver.
脂肪肝となる原因の1つとして、飲酒がある。アルコールは、肝臓で解毒されて体外に排出されるが、解毒の過程で肝臓の働きに異常が生じると、肝臓中に脂肪が蓄積してしまうことがある。飲酒が原因でできる脂肪肝は、アルコール性脂肪肝と呼ばれる。また、肥満、糖尿病および脂質異常症（高脂血症）などによりインスリンの働きが低下して脂肪肝となることがある。このような脂肪肝は、非アルコール性脂肪肝と呼ばれる。 One of the causes of fatty liver is drinking alcohol. Alcohol is detoxified by the liver and excreted from the body, but if abnormalities occur in the liver function during the detoxification process, fat may accumulate in the liver. Fatty liver caused by drinking is called alcoholic fatty liver. Also, obesity, diabetes, dyslipidemia (hyperlipidemia), etc., may reduce insulin function and cause fatty liver. Such fatty liver is called non-alcoholic fatty liver.
脂肪肝は、動脈硬化などの様々な生活習慣病を引き起こすおそれがある。また、脂肪肝は、脂肪性肝炎（アルコール性脂肪性肝炎（ASH）および非アルコール性脂肪性肝炎（NASH）など）となることがあり、さらに肝硬変や肝がんなどに進行することもある。 Fatty liver can cause various lifestyle-related diseases such as arteriosclerosis. In addition, fatty liver may become steatohepatitis (such as alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH)), and may progress to cirrhosis or liver cancer.
脂肪肝を抑制する方法として、特許文献1には、サラシア・レティキュラータおよびサラシア・キネンシスから選択される少なくとも一方の根部の抽出物を有効成分として含むことを特徴とする脂肪肝抑制剤が開示されている。 As a method for suppressing fatty liver, Patent Document 1 discloses a fatty liver inhibitor characterized by containing, as an active ingredient, an extract of at least one root selected from Salacia reticulata and Salacia chinensis. Yes.
上述したように、脂肪肝は、様々な生活習慣病を引き起こしたり、肝硬変や肝がんに進行したりするおそれがあるため、脂肪肝を効率的に抑制できる薬剤の開発が望まれている。本発明は、肝臓における脂肪滴の肥大化を抑制することが可能な新規の薬剤を提供することを目的とする。 As described above, since fatty liver may cause various lifestyle-related diseases or progress to cirrhosis or liver cancer, development of a drug capable of efficiently suppressing fatty liver is desired. An object of this invention is to provide the novel chemical | medical agent which can suppress the enlargement of the lipid droplet in a liver.
本発明者らは、アルクチゲニンを投与したレプチン受容体欠損モデルマウスの血中トリグリセリドおよび遊離脂肪酸の濃度がControl群と比較して減少することを見出した。そこで、肝臓組織を顕微鏡観察したところ、アルクチゲニン投与群（AG群）では、Control群と比較して脂肪滴が小さく、また数が少ないことを見出した。さらに、AG群では、Control群と比較して脂肪酸合成酵素の発現を制御するLXRαおよびSREBP1cをコードする遺伝子の発現量が減少していることを見出し、本発明を完成させた。 The inventors of the present invention have found that the blood triglyceride and free fatty acid concentrations of leptin receptor-deficient model mice administered with arctigenin are decreased compared to the control group. Therefore, when the liver tissue was observed with a microscope, it was found that the argigeninin-administered group (AG group) had smaller lipid droplets and a smaller number than the Control group. Furthermore, in the AG group, it was found that the expression levels of genes encoding LXRα and SREBP1c that control the expression of fatty acid synthase were reduced compared to the Control group, and the present invention was completed.
本発明は、アルクチゲニンおよび／またはアルクチインを有効成分として含有する、肝臓の脂肪滴の肥大化抑制剤を提供する。 The present invention provides an agent for suppressing enlargement of liver lipid droplets, which contains arctigenin and / or arctiin as an active ingredient.
また本発明は、アルクチゲニンおよび／またはアルクチインを有効成分として含有する、肝臓の脂肪滴の肥大化抑制用組成物を提供する。 The present invention also provides a composition for suppressing enlargement of lipid droplets in the liver, which contains arctigenin and / or arctiin as an active ingredient.
また本発明は、アルクチゲニンおよび／またはアルクチインを、ゴボウ、ゴボウシ、ゴボウスプラウトもしくはレンギョウまたはこれらの抽出物として含有する、上記肝臓の脂肪滴の肥大化抑制用組成物を提供する。 The present invention also provides the composition for suppressing the enlargement of lipid droplets in the liver, which contains arctigenin and / or arctiin as burdock, burdock, burdock sprout or forsythia or an extract thereof.
また本発明は、アルクチゲニンおよび／またはアルクチインを有効成分として含有する、肝臓の脂肪滴の肥大化抑制用食品組成物を提供する。 The present invention also provides a food composition for suppressing enlargement of lipid droplets in the liver, which contains arctigenin and / or arctiin as an active ingredient.
また本発明は、アルクチゲニンおよび／またはアルクチインを、ゴボウ、ゴボウシ、ゴボウスプラウトもしくはレンギョウまたはこれらの抽出物として含有する、上記肝臓の脂肪滴の肥大化抑制用食品組成物を提供する。 The present invention also provides the above-mentioned food composition for suppressing the enlargement of lipid droplets in the liver, which contains arctigenin and / or arcticin as burdock, burdock, burdock sprout or forsythia or an extract thereof.
また本発明は、アルクチゲニンおよび／またはアルクチインを有効成分として含有する、LXRαまたはSREBP1cの発現抑制剤を提供する。 The present invention also provides an expression inhibitor of LXRα or SREBP1c, which contains arctigenin and / or arctiin as an active ingredient.
本発明は、肝臓における脂肪滴の肥大化を効果的に抑制することができるため、脂肪肝や、脂肪肝に由来する様々な生活習慣病、肝硬変および肝がんなどを治療、予防または改善することができる。 Since the present invention can effectively suppress the enlargement of lipid droplets in the liver, it treats, prevents or improves fatty liver, various lifestyle-related diseases derived from fatty liver, cirrhosis and liver cancer, etc. be able to.
本発明は、アルクチゲニンおよび／またはアルクチインを有効成分として含有する、肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物を提供する。 The present invention provides an agent for suppressing enlargement of lipid droplets in the liver and a composition for inhibiting enlargement, which contain arctigenin and / or arctiin as an active ingredient.
本明細書において、「脂肪滴」とは、トリグリセリドおよびコレステロールなどの脂質を貯蔵する細胞小器官をいう。本明細書において「脂肪滴の肥大化を抑制する」とは、たとえば、細胞における所定の大きさ以上の脂肪滴の数を減少させること、細胞内の各脂肪滴の面積の平均値を減少させることおよび個体中の最大の脂肪滴の面積の平均値を減少させることなどを意味する。 As used herein, “fat droplet” refers to an organelle that stores lipids such as triglycerides and cholesterol. In the present specification, “suppressing fat droplet enlargement” means, for example, reducing the number of lipid droplets having a predetermined size or more in a cell, or reducing the average value of the area of each lipid droplet in the cell. And reducing the average value of the area of the largest lipid droplet in an individual.
本発明の肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、アルクチゲニンおよび／またはアルクチインを有効成分として含有する。アルクチゲニンおよびアルクチインは、ゴボウ等の植物に含まれるジフェニルプロパノイド（リグナン類）の1つである。アルクチインは、アルクチゲニンの前駆体であり、生体内で代謝されてアルクチゲニンになることが知られている。アルクチゲニンおよび／またはアルクチインとして、化学的に合成したアルクチゲニンおよび／またはアルクチインを用いてもよいし、植物から単離したアルクチゲニンおよび／またはアルクチインを用いてもよい。また、アルクチゲニンおよび／またはアルクチインとして、アルクチゲニンおよび／またはアルクチインを含む植物そのものまたはこの植物の抽出物を用いてもよい。アルクチゲニンおよび／またはアルクチインを含む植物には、たとえばゴボウ（スプラウト・葉・根茎・ゴボウシ）、アイノコレンギョウ（花・葉・果実・根茎）、チョウセンレンギョウ（花・葉・果実・根茎）、レンギョウ（花・葉・果実・根茎）、シナレンギョウ（花・葉・果実・根茎）、ベニバナ、ヤグルマギク、アメリカオニアザミ、サントリソウ（ギバナアザミ）、カルドン、ゴロツキアザミ、アニウロコアザミ、ゴマ、モミジヒルガオ、シンチクヒメハギ、チョウセンテイカカズラ、テイカカズラ、ムニンテイカカズラ、ヒメテイカカズラ、トウキョウチクトウ、ケテイカカズラ、リョウカオウ、オオケタデ、ヤマザクラ、シロイヌナズナ、アマランス、クルミ、エンバク、スペルタコムギ、軟質コムギ、メキシコイトスギおよびカヤが含まれる。なかでも、ゴボウ（特にゴボウシおよびゴボウスプラウト）およびレンギョウ（特に葉）は、アルクチゲニンおよび／またはアルクチインの含有量が高いため好ましい。植物そのものを用いる場合、生または乾燥して刻んだもの、或いは乾燥して粉末としたものを用いることができる。 The liver fat droplet hypertrophy inhibitor and the hypertrophy suppression composition of the present invention contain arctigenin and / or arctiin as active ingredients. Arctigenin and arctiin are one of diphenylpropanoids (lignans) contained in plants such as burdock. Arctiin is a precursor of arctigenin, and is known to be metabolized in vivo to become arctigenin. As arctigenin and / or arctiin, chemically synthesized arctigenin and / or arctiin may be used, or arctigenin and / or arctiin isolated from a plant may be used. In addition, as arctigenin and / or arctiin, a plant itself containing arctigenin and / or arctiin or an extract of this plant may be used. Plants containing arctigenin and / or arctiin include, for example, burdock (sprouts, leaves, rhizomes, burdock), ayoko forsythia (flowers, leaves, fruits, rhizomes), ginseng (flowers, leaves, fruits, rhizomes), forsythia (flowers)・ Leaf / fruits / rhizome), syringen (flowers / leaves / fruits / rhizome), safflower, cornflower, red-eared thistle, red-eared thrips Datura quail, Teika quail, Muntei casserole, Himeteka quail, Tokyo oleander, Kuteika casserole, Ryo kaiou, Ookade, Yamazakura, Arabidopsis thaliana, Amaranth, walnuts, oats, spelled wheat, soft wheat, Mexican cypress Kaya is included. Of these, burdock (especially burdock and burdock sprout) and forsythia (especially leaves) are preferred because of their high content of arctigenin and / or arctiin. When using the plant itself, raw or dried chopped or dried and powdered can be used.
アルクチゲニンおよび／またはアルクチインとして植物の抽出物を用いる場合、抽出物は、たとえば以下の方法によって植物から調製してもよい。本発明において使用される抽出物は、たとえばアルクチゲニンおよび／またはアルクチインを含む植物から、酵素変換工程および有機溶媒による抽出工程の2段階により抽出してもよい。 When using a plant extract as arctigenin and / or arctiin, the extract may be prepared from the plant by, for example, the following method. The extract used in the present invention may be extracted from a plant containing, for example, arctigenin and / or arctiin by two steps, an enzyme conversion step and an extraction step with an organic solvent.
酵素変換工程は、植物に内在する酵素であるβ-グルコシダーゼにより、該植物に含まれているアルクチインをアルクチゲニンに酵素変換する工程である。具体的には、植物を乾燥し切栽したものを適切な温度に保持することにより内在のβ-グルコシダーゼを作用させて、アルクチインからアルクチゲニンへの反応を進行させる。たとえば、切裁した植物に水などの任意の溶液を加えて、30℃付近の温度（20〜50℃）の間にて攪拌することなどにより、植物を任意の温度に保持することができる。 The enzyme conversion step is a step of enzymatic conversion of arctiin contained in the plant into arctigenin by β-glucosidase, which is an enzyme inherent in the plant. Specifically, a plant obtained by drying and cutting a plant is maintained at an appropriate temperature to cause an endogenous β-glucosidase to act, thereby causing a reaction from arctiin to arctigenin. For example, the plant can be maintained at an arbitrary temperature by adding an arbitrary solution such as water to the cut plant and stirring between temperatures around 30 ° C. (20 to 50 ° C.).
有機溶媒による抽出工程は、任意の適切な有機溶媒を使用して、植物からアルクチゲニンおよびアルクチインを抽出する工程である。すなわち、上記の酵素変換工程によりアルクチゲニンが高含量となった状態で、適切な溶媒を添加して、植物から抽出物（エキス）を抽出する工程である。たとえば、植物に適切な溶媒を添加して、適切な時間加熱攪拌して抽出物を抽出する。また、加熱攪拌以外にも、加熱還流、ドリップ式抽出、浸漬式抽出または加圧式抽出法などの当業者に公知の任意の抽出法を使用して、抽出物を抽出することができる。 The extraction step with an organic solvent is a step of extracting arctigenin and arcthiin from a plant using any appropriate organic solvent. That is, it is a step of extracting an extract (extract) from a plant by adding an appropriate solvent in a state where the content of archigenin is increased by the enzyme conversion step. For example, an appropriate solvent is added to the plant, and the extract is extracted by heating and stirring for an appropriate time. In addition to heating and stirring, the extract can be extracted using any extraction method known to those skilled in the art, such as heating reflux, drip extraction, immersion extraction, or pressure extraction.
アルクチゲニンは水難溶性であることから、有機溶媒を添加することにより、アルクチゲニンの収率を向上させることができる。有機溶媒は、任意の有機溶媒を使用することができる。たとえば、メタノール、エタノールおよびプロパノールなどのアルコール、並びにアセトンを使用することができる。安全性の面を考慮すると、有機溶媒として30％量のエタノールを使用することが好ましい。抽出物から溶媒を留去するとペースト状の濃縮物が得られ、この濃縮物をさらに乾燥すると乾燥物を得ることができる。 Since arctigenin is sparingly soluble in water, the yield of arctigenin can be improved by adding an organic solvent. Any organic solvent can be used as the organic solvent. For example, alcohols such as methanol, ethanol and propanol, and acetone can be used. In view of safety, it is preferable to use 30% amount of ethanol as the organic solvent. When the solvent is distilled off from the extract, a paste-like concentrate is obtained, and when this concentrate is further dried, a dry product can be obtained.
本発明の肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、任意の形態の製剤であることができる。肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、経口投与製剤として、たとえば糖衣錠、バッカル錠、コーティング錠およびチュアブル錠等の錠剤；トローチ剤；丸剤；散剤；硬カプセル剤および軟カプセル剤を含むカプセル剤；顆粒剤；ならびに懸濁剤、乳剤、シロップ剤およびエリキシル剤等の液剤などであることができる。 The liver fat droplet hypertrophy inhibitor and the hypertrophy inhibitor composition of the present invention can be any form of preparation. An agent for inhibiting enlargement of lipid droplets in the liver and a composition for inhibiting enlargement are, for example, tablets such as sugar-coated tablets, buccal tablets, coated tablets and chewable tablets; troches; pills; powders; hard capsules and Capsules including soft capsules; granules; and liquids such as suspensions, emulsions, syrups and elixirs.
また、本発明の肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、静脈注射、皮下注射、腹腔内注射、筋肉内注射、経皮投与、経鼻投与、経肺投与、経腸投与、口腔内投与および経粘膜投与などの非経口投与製剤であることができる。本発明の肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、たとえば、注射剤、経皮吸収テープ、エアゾール剤および坐剤などであることができる。 In addition, the agent for suppressing enlargement of lipid droplets of the liver and the composition for suppressing enlargement of the present invention include intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, nasal administration, transpulmonary administration, transpulmonary administration. It can be a parenteral preparation such as enteral administration, buccal administration and transmucosal administration. The liver fat droplet hypertrophy inhibitor and the hypertrophy inhibitor composition of the present invention can be, for example, an injection, a transdermal absorption tape, an aerosol, and a suppository.
また、本発明の肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、外用剤として提供されることができる。本発明の外用剤は、医薬品および化粧品などであることができる。本発明の外用剤は、皮膚、頭皮、毛髪、粘膜および爪などに適用するための外用剤であることができる。外用剤には、たとえばクリーム剤、軟膏剤、液剤、ゲル剤、ローション剤、乳液剤、エアゾール剤、スティック剤、シートマスク剤、固形剤、泡沫剤、オイル剤およびチック剤等の塗布剤；パップ剤、プラスター剤、テープ剤およびパッチ剤等の貼付剤；並びにスプレー剤などが含まれる。 Moreover, the enlargement inhibitor of fat droplets of the liver and the composition for suppressing enlargement of the present invention can be provided as external preparations. The external preparation of the present invention can be pharmaceuticals and cosmetics. The external preparation of the present invention can be an external preparation for application to skin, scalp, hair, mucous membrane, nails and the like. Examples of external preparations include creams, ointments, liquids, gels, lotions, emulsions, aerosols, sticks, sheet masks, solids, foams, oils, tics, and other coating agents; Adhesives, plasters, adhesives such as tapes and patches; sprays and the like.
また、本発明の肝臓の脂肪滴の肥大化抑制剤および肥大化抑制用組成物は、食用に適した形態であることができ、たとえば固形状、液状、顆粒状、粒状、粉末状、カプセル状、クリーム状およびペースト状などであってもよい。 Further, the lipid fat droplet hypertrophy inhibitor and the hypertrophy suppression composition of the present invention can be in an edible form, for example, solid, liquid, granular, granular, powder, capsule It may be in the form of a cream or paste.
本発明の肥大化抑制用組成物は、医薬品、化粧品および食品などに用いるための組成物であることができる。本発明の肥大化抑制用組成物は、医薬品、化粧品および食品に通常用いられる任意の成分をさらに含むことができる。たとえば、本発明の肥大化抑制用組成物は、薬学的に許容される基剤、担体、賦形剤、結合剤、崩壊剤、滑沢剤および着色剤などをさらに含んでもよい。 The composition for suppressing enlargement of the present invention can be a composition for use in pharmaceuticals, cosmetics, foods and the like. The composition for suppressing enlargement of the present invention can further contain any component usually used in pharmaceuticals, cosmetics and foods. For example, the composition for suppressing enlargement of the present invention may further contain a pharmaceutically acceptable base, carrier, excipient, binder, disintegrant, lubricant, colorant and the like.
肥大化抑制用組成物に使用する担体および賦形剤の例には、乳糖、ブドウ糖、白糖、マンニトール、デキストリン、馬鈴薯デンプン、トウモロコシデンプン、炭酸カルシウム、リン酸カルシウム、硫酸カルシウムおよび結晶セルロースなどを含む。 Examples of carriers and excipients used in the composition for suppressing hypertrophy include lactose, glucose, sucrose, mannitol, dextrin, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate and crystalline cellulose.
結合剤の例には、デンプン、ゼラチン、シロップ、トラガントゴム、ポリビニルアルコール、ポリビニルエーテル、ポリビニルピロリドン、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロースおよびカルボキシメチルセルロースなどを含む。 Examples of binders include starch, gelatin, syrup, tragacanth gum, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropylcellulose, methylcellulose, ethylcellulose and carboxymethylcellulose.
崩壊剤の例には、デンプン、寒天、ゼラチン末、結晶セルロース、炭酸カルシウム、炭酸水素ナトリウム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウムおよびカルボキシメチルセルロースカルシウムなどを含む。 Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium and the like.
滑沢剤の例には、ステアリン酸マグネシウム、水素添加植物油、タルクおよびマクロゴールなどを含む。着色剤は、医薬品、化粧品および食品に添加することが許容されている任意の着色剤を使用することができる。 Examples of lubricants include magnesium stearate, hydrogenated vegetable oil, talc and macrogol. As the colorant, any colorant allowed to be added to pharmaceuticals, cosmetics and foods can be used.
また、肥大化抑制用組成物は、必要に応じて、白糖、ゼラチン、精製セラック、ゼラチン、グリセリン、ソルビトール、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、フタル酸セルロースアセテート、ヒドロキシプロピルメチルセルロースフタレート、メチルメタクリレートおよびメタアクリル酸重合体などで一層以上の層で被膜してもよい。 In addition, the composition for suppressing enlargement may be sucrose, gelatin, purified shellac, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate as necessary. Further, it may be coated with one or more layers such as methyl methacrylate and methacrylic acid polymer.
また、肥大化抑制用組成物は、必要に応じて、pH調節剤、緩衝剤、安定化剤、保存剤、防腐剤、希釈剤、コーティング剤、甘味剤、香料および可溶化剤などを添加してもよい。 In addition, the composition for suppressing enlargement is added with a pH regulator, a buffer, a stabilizer, a preservative, a preservative, a diluent, a coating agent, a sweetener, a fragrance, a solubilizing agent, and the like as necessary. May be.
本発明はまた、本発明の肥大化抑制用組成物を含有する医薬品を提供する。本発明の医薬品は、肝臓の脂肪滴の肥大化を抑制するための医薬品であることができる。また、本発明の医薬品は、脂肪滴肥大に関連する種々の症状を治療、改善および予防するための医薬品であることができ、たとえば脂肪肝並びに脂肪肝に関連する動脈硬化、脂肪性肝炎、肝硬変および肝がんなどの種々の疾患および状態を治療、改善および予防するための医薬品であることができる。 The present invention also provides a pharmaceutical comprising the composition for suppressing enlargement of the present invention. The pharmaceutical of the present invention can be a pharmaceutical for suppressing enlargement of liver lipid droplets. In addition, the medicament of the present invention can be a medicament for treating, ameliorating and preventing various symptoms related to lipid droplet enlargement, for example, fatty liver and arteriosclerosis associated with fatty liver, steatohepatitis, cirrhosis. And pharmaceuticals for treating, ameliorating and preventing various diseases and conditions such as liver cancer.
本発明はまた、アルクチゲニンおよび／またはアルクチインを有効成分として含有する肥大化抑制用食品組成物を提供する。本発明の肥大化抑制用食品組成物は、上述した肥大化抑制剤および肥大化抑制用組成物と同様に構成されることができる。本発明の食品組成物は、脂肪肝並びに脂肪肝に関連する動脈硬化、脂肪性肝炎、肝硬変および肝がんなどの種々の疾患および状態を改善または予防するための食品組成物であることができる。 The present invention also provides a food composition for inhibiting hypertrophy containing architigenin and / or archtiin as active ingredients. The food composition for suppressing enlargement of the present invention can be configured in the same manner as the above-described agent for suppressing enlargement and composition for suppressing enlargement. The food composition of the present invention can be a food composition for improving or preventing various diseases and conditions such as fatty liver and fatty liver-related arteriosclerosis, steatohepatitis, cirrhosis and liver cancer. .
本明細書において「食品組成物」には、一般的な飲食品だけでなく、病者用食品、健康食品、機能性食品、特定保健用食品、栄養補助食品およびサプリメントなどが含まれる。一般的な飲食品には、たとえば各種飲料、各種食品、加工食品、液状食品（スープ等）、調味料、栄養ドリンクおよび菓子類などが含まれる。本明細書において「加工食品」とは、天然の食材（動物および植物など）に対し加工および／または調理を施したものをいい、たとえば肉加工品、野菜加工品、果実加工品、冷凍食品、レトルト食品、缶詰食品、瓶詰食品およびインスタント食品などが含まれる。本発明の食品組成物は、グルカゴンを抑制する旨の表示を付した食品であってもよい。また、本発明の食品組成物は、袋および容器等に封入された形態で提供されてもよい。本発明において使用する袋および容器は、食品に通常使用される任意の袋および容器であることができる。 In the present specification, the “food composition” includes not only general foods and drinks but also foods for patients, health foods, functional foods, foods for specified health use, dietary supplements and supplements. Common foods and drinks include, for example, various beverages, various foods, processed foods, liquid foods (soups, etc.), seasonings, energy drinks, and confectionery. In the present specification, the “processed food” refers to a product obtained by processing and / or cooking natural ingredients (animals, plants, etc.), such as processed meat products, processed vegetable products, processed fruit products, frozen foods, Includes retort foods, canned foods, bottled foods and instant foods. The food composition of the present invention may be a food with an indication that glucagon is suppressed. Moreover, the food composition of the present invention may be provided in a form enclosed in a bag, a container or the like. The bags and containers used in the present invention can be any bags and containers normally used for food.
本発明の肥大化抑制剤、肥大化抑制用組成物および肥大化抑制用食品組成物におけるアルクチゲニンおよび／またはアルクチインの含有量は、脂肪滴の肥大化を抑制する効果を発揮できる量であればよく、適用する対象、目的および投与方法（摂取方法）に応じて適宜設定することができる。たとえばヒトに経口摂取させる場合、好ましくはアルクチゲニンおよび／またはアルクチインを1日あたりの摂取量が10〜2000mgとなるように含むことができる。 The content of arctigenin and / or arctiin in the hypertrophy inhibitor, the hypertrophy suppression composition, and the hypertrophy suppression food composition of the present invention may be any amount that can exert the effect of suppressing the enlargement of fat droplets. Depending on the subject to be applied, purpose and administration method (intake method), it can be set as appropriate. For example, when orally ingested by humans, it is preferable to include archigenin and / or archtiin so that the daily intake is 10 to 2000 mg.
本発明はまた、アルクチゲニンおよび／またはアルクチインを有効成分として含有する、LXRαまたはSREBP1cの発現抑制剤を提供する。LXRαは、肝臓にある核内受容体の1つであり、活性化されるとSREBP1c（Sterol regulatory element-binding protein）の発現を上昇させる、核内転写因子である。SREBP1cは、脂肪酸合成酵素であるFAS（fatty acid synthase）およびACC（acetyl-CoA carboxylase）などの発現を制御する転写因子である。 The present invention also provides an LXRα or SREBP1c expression inhibitor containing arctigenin and / or arctiin as an active ingredient. LXRα is one of the nuclear receptors in the liver and is a nuclear transcription factor that increases the expression of SREBP1c (Sterol regulatory element-binding protein) when activated. SREBP1c is a transcription factor that regulates the expression of fatty acid synthase, such as FAS (fatty acid synthase) and ACC (acetyl-CoA carboxylase).
本明細書において「発現を抑制する」とは、たとえばタンパク質をコードする遺伝子の転写産物の量を減少させることおよびタンパク質の量を減少させることなどを意味する。 As used herein, “suppressing expression” means, for example, decreasing the amount of a transcript of a gene encoding a protein and decreasing the amount of a protein.
本発明のLXRαまたはSREBP1cの発現抑制剤は、アルクチゲニンおよび／またはアルクチインを、ゴボウ、ゴボウシ、ゴボウスプラウトもしくはレンギョウまたはこれらの抽出物として含有してもよい。また、本発明のLXRαまたはSREBP1cの発現抑制剤は、上述した本発明の肥大化抑制剤、肥大化抑制用組成物および肥大化抑制用食品組成物と同様に構成されることができる。 The expression inhibitor of LXRα or SREBP1c of the present invention may contain arctigenin and / or arctiin as burdock, burdock, burdock sprout or forsythia, or an extract thereof. Moreover, the expression inhibitor of LXRα or SREBP1c of the present invention can be configured in the same manner as the enlargement inhibitor, the composition for suppressing enlargement and the food composition for suppressing enlargement of the present invention described above.
本発明のLXRαまたはSREBP1cの発現抑制剤は、LXRαおよび／またはSREBP1cの発現を抑制することにより、脂肪酸合成酵素などの発現を抑制することができる。したがって、本発明のLXRαまたはSREBP1cの発現抑制剤は、肝臓の脂肪滴の肥大化を抑制し、脂肪肝を治療、予防または改善することができる。 The LXRα or SREBP1c expression inhibitor of the present invention can suppress the expression of fatty acid synthase or the like by suppressing the expression of LXRα and / or SREBP1c. Therefore, the LXRα or SREBP1c expression inhibitor of the present invention can suppress the enlargement of liver lipid droplets, and can treat, prevent or improve fatty liver.
以下に実施例を示し、本発明の実施の形態についてさらに詳しく説明するが、本発明は以下の実施例に限定されるものではない。 Hereinafter, examples will be shown and the embodiment of the present invention will be described in more detail. However, the present invention is not limited to the following examples.
（酵素活性の測定）
ゴボウシ中のβ−グルコシダーゼ活性は、以下の方法で測定した。産地やロットが異なるゴボウシをウイレー氏粉砕機により粉砕し、このゴボウシ粉砕品0.1gを10mLの水で希釈し、試料溶液とした。
(Measurement of enzyme activity)
The β-glucosidase activity in burdock was measured by the following method. A burdock of different origin and lot was pulverized by Mr. Willet pulverizer, and 0.1 g of this pulverized burdock was diluted with 10 mL of water to prepare a sample solution.
基質溶液として、p-ニトロフェニル-β-D-グルコピラノシド0.15gに水を加えて25mLに定容し、20mmol/L p-ニトロフェニル-β-D-グルコピラノシド水溶液を調製した。0.1mol/L酢酸緩衝液1mLに20mmol/L p-ニトロフェニル-β-D-グルコピラノシド水溶液0.5mLを加えて、反応混液を調製し、37℃で約5分予備加熱を行った。 As a substrate solution, water was added to 0.15 g of p-nitrophenyl-β-D-glucopyranoside and the volume was adjusted to 25 mL to prepare a 20 mmol / L p-nitrophenyl-β-D-glucopyranoside aqueous solution. A reaction mixture was prepared by adding 0.5 mL of 20 mmol / L p-nitrophenyl-β-D-glucopyranoside aqueous solution to 1 mL of 0.1 mol / L acetate buffer, and pre-heated at 37 ° C. for about 5 minutes.
反応混液に試料溶液0.5mL加えて37℃で15分反応させた後、反応停止液である0.2mol/L炭酸ナトリウム水溶液を2mL加えて反応を停止させた。この液の400nmにおける吸光度を測定し、酵素反応を行わないブランク溶液からの変化量から下式により酵素活性を求めた。
酵素活性（U/g）＝（試料溶液の吸光度-ブランク溶液の吸光度）×4mL×1／18.1（p-ニトロフェノールの上記測定条件下でのミリモル分子吸光係数：cm2／μmol)×1／光路長(cm)×1／反応時間（分）×1／0.5mL×1／試料溶液濃度（g／mL）
After adding 0.5 mL of the sample solution to the reaction mixture and reacting at 37 ° C. for 15 minutes, 2 mL of 0.2 mol / L sodium carbonate aqueous solution as a reaction stop solution was added to stop the reaction. The absorbance at 400 nm of this solution was measured, and the enzyme activity was determined from the amount of change from the blank solution in which the enzyme reaction was not performed according to the following formula.
Enzyme activity (U / g) = (absorbance of sample solution−absorbance of blank solution) × 4 mL × 1 / 18.1 (molar molecular extinction coefficient of p-nitrophenol under the above measurement conditions: cm 2 / μmol) × 1 / Optical path length (cm) x 1 / reaction time (min) x 1 / 0.5mL x 1 / sample solution concentration (g / mL)
（実施例1 ゴボウシ抽出物の製造1）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシからエキス（抽出物）を抽出した。ゴボウシ（酵素活性8.23U/g）を切裁し、9.5mmの篩を全通するものをさらに0.85mmの篩に通し、75％が残ることを確認した。このゴボウシ細切80kgを29〜33℃に保温した水560Lに加えて30分間攪拌した。次いで、エタノール265Lを加えて85℃に昇温し、さらに60分間加熱還流した。この溶液を遠心分離し、ゴボウシ抽出液を得た。この操作を2回繰り返して得られた抽出液を合わせて、減圧濃縮し、抽出物固形分に対してデキストリン25％量を加えて、噴霧乾燥した。アルクチゲニンおよびアルクチイン含量は、それぞれ6.2％および7.1％であり、アルクチゲニン／アルクチイン（重量比）＝0.89のゴボウシ抽出物粉末（デキストリン20％含有）が得られた。
(Example 1 Production of burdock extract 1)
As an example of the composition for suppressing glucagon of the present invention, an extract (extract) was extracted from a gobo cow. The burdock (enzyme activity 8.23 U / g) was cut, and the whole 9.5 mm sieve was passed through a 0.85 mm sieve to confirm that 75% remained. 80 kg of this burdock slice was added to 560 L of water kept at 29-33 ° C. and stirred for 30 minutes. Next, 265 L of ethanol was added, the temperature was raised to 85 ° C., and the mixture was further heated to reflux for 60 minutes. This solution was centrifuged to obtain a burdock extract. Extracts obtained by repeating this operation twice were combined, concentrated under reduced pressure, added with a 25% amount of dextrin based on the solid content of the extract, and spray-dried. The contents of arctigenin and arcthiin were 6.2% and 7.1%, respectively, and a burdock extract powder (containing 20% dextrin) having an arctigenin / arctiin (weight ratio) = 0.89 was obtained.
（実施例2 ゴボウシ抽出物の製造2）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシからエキス（抽出物）を抽出した。ゴボウシ（酵素活性8.23U/g）を切裁し、9.5mmの篩を全通するものをさらに0.85mmの篩に通し、75％が残ることを確認した。このゴボウシ細切80kgを30〜33℃に保温した水560Lに加えて30分間攪拌した後、エタノール265Lを加えて85℃に昇温し、さらに30分間加熱還流した。この溶液を遠心分離し、ゴボウシ抽出液を得た。この操作を2回繰り返して得られた抽出液を合わせて、減圧濃縮し、抽出物固形分に対してデキストリン25％量を加えて、噴霧乾燥した。アルクチゲニンおよびアルクチイン含量は、それぞれ6.0％および6.8％であり、アルクチゲニン／アルクチイン（重量比）＝0.87のゴボウシ抽出物粉末（デキストリン20％含有）が得られた。
(Example 2 Production of burdock extract 2)
As an example of the composition for suppressing glucagon of the present invention, an extract (extract) was extracted from a gobo cow. The burdock (enzyme activity 8.23 U / g) was cut, and the whole 9.5 mm sieve was passed through a 0.85 mm sieve to confirm that 75% remained. After adding 80 kg of this burdock chopped to 560 L of water kept at 30 to 33 ° C. and stirring for 30 minutes, 265 L of ethanol was added, the temperature was raised to 85 ° C., and the mixture was further heated to reflux for 30 minutes. This solution was centrifuged to obtain a burdock extract. Extracts obtained by repeating this operation twice were combined, concentrated under reduced pressure, added with a 25% amount of dextrin based on the solid content of the extract, and spray-dried. Arctigenin and arcthiin contents were 6.0% and 6.8%, respectively, and burdock extract powder (containing 20% dextrin) having an arctigenin / arctiin (weight ratio) = 0.87 was obtained.
（実施例3 ゴボウシ抽出物の製造3）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシからエキス（抽出物）を抽出した。ゴボウシ（酵素活性7.82U/g）を切裁し、9.5mmの篩を全通するものをさらに0.85mmの篩に通し、75％が残ることを確認した。このゴボウシ細切80kgを30〜32℃に保温した水560Lに加えて40分間攪拌した後、60分後にエタノール258Lを加えて85℃に昇温し、さらに30分間加熱還流した。この液を遠心分離し、ゴボウシ抽出液を得た。この操作を2回繰り返して得られた抽出液を合わせて、減圧濃縮し、抽出物固形分に対してデキストリン25％量を加えて、噴霧乾燥した。アルクチゲニンおよびアルクチイン含量は、それぞれ6.2％および6.7％であり、アルクチゲニン／アルクチイン（重量比）＝0.93のゴボウシ抽出物粉末（デキストリン20％含有）が得られた。
(Example 3 Production of burdock extract 3)
As an example of the composition for suppressing glucagon of the present invention, an extract (extract) was extracted from a gobo cow. The burdock (enzyme activity: 7.82 U / g) was cut, and all the 9.5 mm sieve was passed through the 0.85 mm sieve to confirm that 75% remained. This burdock 80 kg was added to 560 L of water kept at 30 to 32 ° C. and stirred for 40 minutes, and then 60 minutes later, 258 L of ethanol was added, the temperature was raised to 85 ° C., and the mixture was further refluxed for 30 minutes. This solution was centrifuged to obtain a burdock extract. Extracts obtained by repeating this operation twice were combined, concentrated under reduced pressure, added with a 25% amount of dextrin based on the solid content of the extract, and spray-dried. Arctigenin and arctiin contents were 6.2% and 6.7%, respectively, and an argotigenin / arctiin (weight ratio) = 0.93 burdock extract powder (containing 20% dextrin) was obtained.
（実施例4 ゴボウシ抽出物の製造4）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシからエキス（抽出物）を抽出した。ゴボウシ（酵素活性7.82U/g）を切裁し、9.5mmの篩を全通するものをさらに0.85mmの篩に通し、75％が残ることを確認した。このゴボウシ細切80kgを30〜32℃に保温した水560Lに加えて30分間攪拌した後、エタノール253Lを加えて85℃に昇温し、さらに40分間加熱還流した。この液を遠心分離し、得られた抽出液を得た。この操作を2回繰り返して得られた抽出液を合わせて、減圧濃縮し、抽出物固形分に対してデキストリン25％量を加えて、噴霧乾燥した。アルクチゲニンおよびアルクチイン含量は、それぞれ6.4％および7.2％であり、アルクチゲニン／アルクチイン（重量比）＝0.89のゴボウシ抽出物粉末（デキストリン20％含有）が得られた。
(Example 4 Production of burdock extract 4)
As an example of the composition for suppressing glucagon of the present invention, an extract (extract) was extracted from a gobo cow. The burdock (enzyme activity: 7.82 U / g) was cut, and all the 9.5 mm sieve was passed through the 0.85 mm sieve to confirm that 75% remained. After adding 80 kg of this burdock chopped to 560 L of water kept at 30 to 32 ° C. and stirring for 30 minutes, ethanol 253 L was added, the temperature was raised to 85 ° C., and the mixture was further heated to reflux for 40 minutes. This liquid was centrifuged to obtain the resulting extract. Extracts obtained by repeating this operation twice were combined, concentrated under reduced pressure, added with a 25% amount of dextrin based on the solid content of the extract, and spray-dried. Arctigenin and arctiin contents were 6.4% and 7.2%, respectively, and burdock extract powder (containing 20% dextrin) having arctigenin / arctiin (weight ratio) = 0.89 was obtained.
（実施例5 シナレンギョウ葉抽出物の製造1）
本発明のグルカゴン抑制用組成物の一実施例として、シナレンギョウ葉からエキス（抽出物）を抽出した。アルクチイン2.53％およびアルクチゲニン0.76％を含有するレンギョウ葉小刻み50gに水350mLを加えて37℃で30分間保温後、エタノール150mLを添加し30分間加熱抽出した。この溶液を100メッシュ篩を用いて固液分離し、凍結乾燥を行うことにより、アルクチゲニン含量が5.62％のシナレンギョウ葉抽出物18.62gを得た。
(Example 5 Production of Synaxenix leaf extract 1)
As an example of the glucagon-suppressing composition of the present invention, an extract (extract) was extracted from Sinalengyo leaves. 350 mL of water was added to 50 g of forsythia leaf chopping containing 2.53% of arctiin and 0.76% of arctigenin, and the mixture was incubated at 37 ° C. for 30 minutes, and then 150 mL of ethanol was added and extracted by heating for 30 minutes. This solution was subjected to solid-liquid separation using a 100-mesh sieve and freeze-dried to obtain 18.62 g of Sinalengyo leaf extract having an arctigenin content of 5.62%.
（実施例6 シナレンギョウ葉抽出物の製造2）
本発明のグルカゴン抑制用組成物の一実施例として、シナレンギョウ葉からエキス（抽出物）を抽出した。アルクチイン7.38％およびアルクチゲニン0.78％を含有するレンギョウ葉小刻み720gに水5Lを加えて37°Cで30分間保温後、エタノール2.16Lを添加し30分間加熱抽出した。この溶液を100メッシュ篩を用いて固液分離し、凍結乾燥を行うことにより、アルクチゲニン含量が9.55％のシナレンギョウ葉抽出物343.07gを得た。
(Example 6: Production of Sinalengyo leaf extract 2)
As an example of the glucagon-suppressing composition of the present invention, an extract (extract) was extracted from Sinalengyo leaves. 5 L of water was added to 720 g of forsythia leaf chopping containing 7.38% arctiin and 0.78% arctigenin, and incubated at 37 ° C for 30 minutes, followed by addition of 2.16 L of ethanol and extraction by heating for 30 minutes. This solution was subjected to solid-liquid separation using a 100 mesh sieve and freeze-dried to obtain 343.07 g of Sinalengyo leaf extract having 9.55% arctigenin content.
（実施例7 ゴボウシ抽出物粉末配合顆粒剤）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシ抽出物を用いて顆粒剤を製造した。「日局」製剤総則、顆粒剤の項に準じて顆粒剤を製造した。すなわち、下記（1）〜（3）の成分をとり、顆粒状に製した。これを1.5ｇずつアルミラミネートフィルムに充填し、1包あたりゴボウシ抽出物粉末を0.5ｇ含有する顆粒剤を得た。
(Example 7 granule containing burdock extract powder)
As an example of the composition for suppressing glucagon of the present invention, a granule was produced using a gobo cow extract. Granules were produced in accordance with the “Japan Pharmacopoeia” general rules for preparations and granules. That is, the following components (1) to (3) were taken and made into granules. This was filled into an aluminum laminate film in an amount of 1.5 g to obtain granules containing 0.5 g of burdock extract powder per packet.
（1）実施例2のゴボウシ抽出物粉末 33.3％
（2）乳糖 65.2％
（3）ヒドロキシプロピルセルロース 1.5％
合計 100％
(1) Gobo cow extract powder of Example 2 33.3%
(2) Lactose 65.2%
(3) Hydroxypropylcellulose 1.5%
Total 100%
（実施例8 ゴボウシ抽出物粉末配合顆粒剤）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシ抽出物を用いて顆粒剤を製造した。「日局」製剤総則、顆粒剤の項に準じて顆粒剤を製造した。すなわち、下記（1）〜（3）の成分をとり、顆粒状に製した。これを3.0ｇずつアルミラミネートフィルムに充填し、1包あたりゴボウシ抽出物粉末を2ｇ含有する顆粒剤を得た。
(Example 8 granule containing burdock extract powder)
As an example of the composition for suppressing glucagon of the present invention, a granule was produced using a gobo cow extract. Granules were produced in accordance with the “Japan Pharmacopoeia” general rules for preparations and granules. That is, the following components (1) to (3) were taken and made into granules. Each 3.0 g of this was filled in an aluminum laminate film to obtain granules containing 2 g of burdock extract powder per packet.
（1）実施例2のゴボウシ抽出物粉末 66.7％
（2）乳糖 30.3％
（3）ヒドロキシプロピルセルロース 3.0％
合計 100％
(1) Gobo cow extract powder of Example 2 66.7%
(2) Lactose 30.3%
(3) Hydroxypropylcellulose 3.0%
Total 100%
（実施例9 ゴボウシ抽出物粉末配合錠剤）
本発明のグルカゴン抑制用組成物の一実施例として、ゴボウシ抽出物を用いて錠剤を製造した。「日局」製剤総則、錠剤の項に準じて錠剤を製した。すなわち、下記（1）〜（6）の成分をとり、錠剤を得た。
Example 9 Tablets containing burdock extract powder
As one example of the glucagon-suppressing composition of the present invention, tablets were produced using a gobo cow extract. Tablets were produced in accordance with the “Japanese Pharmacopoeia” General Rules for Preparations and Tablets. That is, the following components (1) to (6) were taken to obtain tablets.
（1）実施例2のゴボウシ抽出物粉末 37.0％
（2）結晶セルロース 45.1％
（3）カルメロースカルシウム 10.0％
（4）クロスポピドン 3.5％
（5）含水二酸化ケイ素 3.4％
（6）ステアリン酸マグネシウム 1.0％
合計 100％
(1) Burdock extract powder of Example 2 37.0%
(2) Crystalline cellulose 45.1%
(3) Carmellose calcium 10.0%
(4) Crospopidone 3.5%
(5) Hydrous silicon dioxide 3.4%
(6) Magnesium stearate 1.0%
Total 100%
（実施例10 肝臓の脂肪滴に対するアルクチゲニンの効果）
［実験動物］
レプチン受容体欠損モデルである、5週齢の雄性db/dbマウス（BKS.Cg-+Leprdb/+Leprdb/Jcl、日本クレア社より購入）を使用して、1週間の予備飼育後に実験を開始した。動物は温度23.0±5℃、湿度50.0±10%、12時間の明暗サイクルの環境下で飼育した。動物実験は慶應義塾大学動物実験委員会の承認を得て、慶應義塾大学動物実験規定に基づき実施した。
(Example 10 Effect of arctigenin on liver lipid droplets)
[Experimental animals]
Using a leptin receptor-deficient model, a 5-week-old male db / db mouse (BKS.Cg- + Leprdb / + Leprdb / Jcl, purchased from CLEA Japan) did. The animals were kept in an environment of a temperature of 23.0 ± 5 ° C., a humidity of 50.0 ± 10%, and a 12 hour light / dark cycle. Animal experiments were approved by the Animal Experiment Committee of Keio University and conducted based on the Keio University Animal Experiment Rules.
［実験方法］
予備飼育後に、マウスを（a）Control群および（b）アルクチゲニン投与群（AG群）の2群にわけ（各群n=8）、Control群には精製飼料（AIN-93G）を、AG群にはアルクチゲニン（>98.0%）0.2%配合の精製飼料を9週間自由摂取させた。投与6週目に尾静脈より採血を行い、血中TGおよび血中飽和脂肪酸濃度を測定した。投与終了後、18時間の絶食を行い、麻酔下で腹部大静脈より採血し、肝臓を採取した。採取した肝臓は一部を遺伝子解析用、一部を組織切片用に分けた。
[experimental method]
After preliminary breeding, the mice were divided into two groups (n) (a) Control group and (b) architigenin administration group (AG group) (each group n = 8), and purified feed (AIN-93G) was added to the Control group, AG group Was allowed free intake of refined feed containing 0.2% arguchigenin (> 98.0%) for 9 weeks. Six weeks after administration, blood was collected from the tail vein, and blood TG and blood saturated fatty acid concentrations were measured. After the administration, the animals were fasted for 18 hours, and blood was collected from the abdominal vena cava under anesthesia, and the liver was collected. The collected liver was partly divided for gene analysis and partly for tissue section.
［血中脂質の測定］
血中のトリグリセリド（TG）および遊離脂肪酸の濃度は、それぞれ、デタミナーL TGII（協和メデックス株式会社製）およびNEFA C-テストワコー（和光純薬工業株式会社製）を用いて測定した。
[Measurement of blood lipids]
The concentrations of triglyceride (TG) and free fatty acid in the blood were measured using Determiner L TGII (manufactured by Kyowa Medex Co., Ltd.) and NEFA C-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.), respectively.
図1は、各群の血中TG濃度（mg/dL）を示す。また、図2は、各群の血中遊離脂肪酸濃度（μEq/L）を示す。図1および図2における値は、6匹の平均±標準誤差（Mean±S.E.M）を表す。Student’s t-testの結果、p値が0.05より小さい場合には「*」を付した。図1および図2に示すように、AG群では、Control群と比較して血中TG濃度および血中遊離脂肪酸濃度が有意に低かった。 FIG. 1 shows the blood TG concentration (mg / dL) in each group. FIG. 2 shows the blood free fatty acid concentration (μEq / L) in each group. The values in FIGS. 1 and 2 represent the mean ± standard error (Mean ± S.E.M) of 6 animals. As a result of Student ’s t-test, “*” was added when the p-value was less than 0.05. As shown in FIGS. 1 and 2, in the AG group, the blood TG concentration and the blood free fatty acid concentration were significantly lower than those in the Control group.
［肝臓における脂肪滴蓄積］
Control群およびAG群の肝臓組織を10%ホルマリン液により固定後、組織切片を作製し顕微鏡下で観察した。図3はControl群、図4はAG群の肝臓組織の顕微鏡画像を表す図である。図3および図4に示すように、AG群では、Control群と比較して脂肪滴が小さく、また数が少なかった。
[Liquid droplet accumulation in the liver]
After fixing the liver tissues of the Control group and the AG group with 10% formalin solution, tissue sections were prepared and observed under a microscope. FIG. 3 is a view showing a microscope image of the liver tissue of the Control group, and FIG. 4 is a view of the AG group. As shown in FIGS. 3 and 4, in the AG group, the number of lipid droplets was smaller and the number was smaller than that in the Control group.
次に、各個体についてランダムに5枚の画像を取得し、画像解析ソフトImageJを用いて各群の肝臓組織における脂肪滴数、脂肪滴面積および各個体中の最大サイズの脂肪滴面積を測定した。図5は各群の肝臓組織における30μm2より大きい脂肪滴数を示す。図6は、各群の肝臓組織における脂肪滴面積の平均値（μm2）を示す。図7は、各群の肝臓組織における最大サイズの脂肪滴面積の平均値（μm2）を示す。AG群における脂肪滴数、脂肪滴面積の平均値および各個体中の最大サイズの脂肪滴面積の平均値はいずれも、Control群と比較して低かった。 Next, five images were randomly acquired for each individual, and the number of lipid droplets, the lipid droplet area, and the maximum size of the lipid droplet area in each individual were measured using image analysis software ImageJ. . FIG. 5 shows the number of lipid droplets greater than 30 μm 2 in the liver tissue of each group. FIG. 6 shows the average value (μm 2 ) of the lipid droplet area in the liver tissue of each group. FIG. 7 shows the average value (μm 2 ) of the largest lipid droplet area in the liver tissue of each group. The number of lipid droplets in the AG group, the average value of the lipid droplet area, and the average value of the maximum size lipid droplet area in each individual were all lower than those in the Control group.
これらの結果から、アルクチゲニンは、肝臓において脂肪滴の肥大化を抑制する作用を有することが示唆された。 From these results, it was suggested that arctigenin has an action of suppressing fat droplet enlargement in the liver.
［脂肪酸合成関連遺伝子の発現量］
各群について、得られた臓器からtotal RNAの抽出およびcDNA合成を行った後、qPCRにより脂肪酸合成関連遺伝子であるSREBP1c、FAS、LXRαおよびACCをコードする遺伝子の発現量を比較した。コントロールとして、18S rRNAを用いた。qPCRのためのプライマーは、18S（F: TTCTGGCCAACGGTCTAGACAAC（配列番号1）、R: CCAGTGGTCTTGGTGTGCTGA（配列番号2））、SREBP1c（F: GGTACCTGCGGGACAGCTTA（配列番号3）、R: CCGTGAGCTACCTGGACTGAA（配列番号4））、FAS（F: CTGGAGGCCTTGCCACTGTA（配列番号5）、R: GCTTGCACCAACACTCAGTTGAC（配列番号6））、LXRα（F: CTGGAGACGTCACGGAGGTACA（配列番号7）、R: TGATGGCAATGAGCAGAGCA（配列番号8））、ACC（F: ACCAACTCCACTGTTTGTGA（配列番号9）、R: CCTTGGAATTCAGGAGAGGA（配列番号10））を用いた。
[Expression level of fatty acid synthesis-related genes]
For each group, total RNA was extracted from the obtained organ and cDNA synthesis was performed, and then the expression levels of genes encoding fatty acid synthesis-related genes SREBP1c, FAS, LXRα and ACC were compared by qPCR. As a control, 18S rRNA was used. Primers for qPCR are 18S (F: TTCTGGCCAACGGTCTAGACAAC (SEQ ID NO: 1), R: CCAGTGGTCTTGGTGTGCTGA (SEQ ID NO: 2)), SREBP1c (F: GGTACCTGCGGGACAGCTTA (SEQ ID NO: 3), R: CCGTGAGCTACCTGGACTGAA (SEQ ID NO: 4)), FAS (F: CTGGAGGCCTTGCCACTGTA (SEQ ID NO: 5), R: GCTTGCACCAACACTCAGTTGAC (SEQ ID NO: 6)), LXRα (F: CTGGAGACGTCACGGAGGTACA (SEQ ID NO: 7), R: TGATGGCAATGAGCAGAGCA (SEQ ID NO: 8)), ACC (F: ACCAACTCCACTGTTTGTGA ), R: CCTTGGAATTCAGGAGAGGA (SEQ ID NO: 10)).
図8はControl群およびAG群におけるSREBP1c、FAS、LXRαおよびACCの発現量を示す。図8における値は、6匹の平均±標準誤差（Mean±S.E.M）を表す。Student’s t-testの結果、p値が0.01より小さい場合には「**」を付した。AG群では、Control群と比較していずれの遺伝子の発現量も低く、SREBP1cに関しては有意に低かった。 FIG. 8 shows the expression levels of SREBP1c, FAS, LXRα and ACC in the Control group and the AG group. The values in FIG. 8 represent the mean ± standard error (Mean ± S.E.M) of 6 animals. As a result of Student ’s t-test, “**” was added when the p-value was smaller than 0.01. In the AG group, the expression level of any gene was low compared to the Control group, and SREBP1c was significantly lower.
これらの結果から、アルクチゲニンは、SREBP1c、FAS、LXRαおよびACCをコードする遺伝子の発現を抑制する作用を有することが示された。 From these results, it was shown that arctigenin has an action of suppressing the expression of genes encoding SREBP1c, FAS, LXRα and ACC.
本発明は、肝臓における脂肪滴の肥大化を抑制することができるため、脂肪肝や、脂肪肝に由来する様々な生活習慣病、肝硬変および肝がんなどを治療、予防または改善するための医薬品および食品などに利用可能である。 The present invention can suppress the enlargement of lipid droplets in the liver, and therefore, a pharmaceutical product for treating, preventing or improving fatty liver, various lifestyle-related diseases derived from fatty liver, cirrhosis and liver cancer, etc. And can be used for foods.
Claims (6)
An expression inhibitor of LXRα or SREBP1c, which contains arctigenin and / or arctiin as an active ingredient.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008297209A (en) * | 2007-05-29 | 2008-12-11 | Yomeishu Seizo Co Ltd | Lipid metabolism-improving composition |
| KR20140146407A (en) * | 2013-06-17 | 2014-12-26 | 한국 한의학 연구원 | A composition for preventing or treating fatty liver disease or obesity, comprising a extract of Arctium lappa Linne, Glycyrrhiza uralensis Fischer, Zingiberis rhizoma Crudus and Magnoliae Cortex |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008297209A (en) * | 2007-05-29 | 2008-12-11 | Yomeishu Seizo Co Ltd | Lipid metabolism-improving composition |
| KR20140146407A (en) * | 2013-06-17 | 2014-12-26 | 한국 한의학 연구원 | A composition for preventing or treating fatty liver disease or obesity, comprising a extract of Arctium lappa Linne, Glycyrrhiza uralensis Fischer, Zingiberis rhizoma Crudus and Magnoliae Cortex |
Non-Patent Citations (5)
| Title |
|---|
| BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 412, JPN6022005768, 2011, pages 197 - 202, ISSN: 0004704827 * |
| INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, vol. 13, no. 3, JPN6022005767, 25 February 2017 (2017-02-25), pages 349 - 357, ISSN: 0004704826 * |
| NUTRIENTS, vol. 7, JPN6021000785, 2015, pages 2440 - 2455, ISSN: 0004704823 * |
| NUTRITION RESEARCH AND PRACTICE, vol. 8, no. 6, JPN6021000784, 2014, pages 655 - 661, ISSN: 0004704824 * |
| SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, vol. 46(11), JPN6021028201, 2011, pages 1381 - 1388, ISSN: 0004704825 * |
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