JP7158021B2 - Composition for promoting CDCA increase, composition for promoting FXR increase and composition for promoting FXR activation - Google Patents
Composition for promoting CDCA increase, composition for promoting FXR increase and composition for promoting FXR activation Download PDFInfo
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Description
本発明は、Ｄ－プシコースを有効成分とする、ＣＤＣＡ増加促進用組成物、ＦＸＲ増加促進用組成物及びＦＸＲ活性化促進用組成物に関する。 The present invention relates to a composition for promoting CDCA increase, a composition for promoting FXR increase and a composition for promoting FXR activation, each containing D-psicose as an active ingredient.
胆汁酸は、胆汁の主成分として含まれる有機酸であり、肝臓でコレステロールから合成される。肝臓で合成された胆汁酸は、胆汁として一旦胆嚢で貯蔵され、胆嚢は、食事摂取により収縮して胆管を通じて十二指腸・小腸にその胆汁を分泌する。十二指腸・小腸に分泌された胆汁酸は、食事由来のコレステロールや脂質をミセル化して生体内に取り込むのに重要な役割を果たすとともに、門脈を経て肝臓に吸収され、再度胆汁の主成分となる。一方、小腸から吸収されなかった胆汁酸は、糞便として排泄される。 Bile acids are organic acids contained as the main component of bile, and are synthesized from cholesterol in the liver. Bile acids synthesized in the liver are temporarily stored in the gallbladder as bile, and the gallbladder contracts with meal intake and secretes the bile into the duodenum and small intestine through the bile duct. Bile acids secreted in the duodenum and small intestine play an important role in micellizing cholesterol and lipids derived from diet and taking them into the body. . On the other hand, bile acids not absorbed from the small intestine are excreted as feces.
以上が胆汁酸の腸肝循環の概要であるが、その胆汁酸の肝臓における濃度は、以下のように調整されている。まず、肝臓内で生成された胆汁酸は、リガンド依存性核内受容体であるファルネソイドＸ受容体（以下、「ＦＸＲ」という。）に結合する。そして、（１）チトクロームＰ４５０ ７Ａ１（ＣＹＰ７Ａ１）を減少させることにより胆汁酸の生合成を低下させ、（２）ナトリウムタウロコール酸共輸送ポリペプチド（ＮＴＣＰ）を減少させて胆汁酸の取り込みを抑え、（３）胆汁酸輸送体（ＢＳＥＰ）を増加させて胆汁酸の排泄を促進し、肝内の胆汁酸が低下するように作用する。つまり、肝臓内胆汁酸濃度は、胆汁酸により活性化されたＦＸＲを介して調節されている。 The above is an overview of the enterohepatic circulation of bile acids, and the concentrations of bile acids in the liver are adjusted as follows. First, bile acids produced in the liver bind to the farnesoid X receptor (hereinafter referred to as "FXR"), which is a ligand-dependent nuclear receptor. (1) decrease bile acid biosynthesis by decreasing cytochrome P450 7A1 (CYP7A1), (2) decrease sodium taurocholate cotransporting polypeptide (NTCP) to suppress bile acid uptake, ( 3) It acts to increase bile acid transporter (BSEP) to promote excretion of bile acid, and to decrease intrahepatic bile acid. Thus, intrahepatic bile acid concentrations are regulated via bile acid-activated FXR.
このＦＸＲは、小腸においても発現し、胆汁酸結合タンパク質（Ｉ－ＢＡＢＰ）の発現を促進することが知られ、胆汁酸がＩ－ＢＡＢＰと結合することにより胆汁酸の取り込みを促進していると考えられる。 This FXR is also expressed in the small intestine and is known to promote the expression of bile acid binding protein (I-BABP), and is believed to promote bile acid uptake by binding to I-BABP. Conceivable.
このように、ＦＸＲは胆汁酸センサーとして機能し、体内の胆汁酸濃度を調節することによって、コレステロールや脂質の体内への取り込みを調節している。したがって、ＦＸＲの増加又は活性化を促すことは、血中脂質濃度上昇に起因する動脈硬化や高脂血症の治療につながると考えられる。そして、胆汁酸のひとつであるケノデオキシコール酸（以下、「ＣＤＣＡ」という。）が、その他の胆汁酸に比してＦＸＲを顕著に活性化することが報告されているため（非特許文献１）、このＣＤＣＡを増加させることができれば、コレステロール・脂質異常症などの疾患の効率的な治療、予防及び改善が期待できる。 Thus, FXR functions as a bile acid sensor and regulates the uptake of cholesterol and lipids into the body by regulating the bile acid concentration in the body. Therefore, promoting the increase or activation of FXR is considered to lead to the treatment of arteriosclerosis and hyperlipidemia caused by elevated blood lipid levels. Since it has been reported that chenodeoxycholic acid (hereinafter referred to as "CDCA"), which is one of the bile acids, significantly activates FXR compared to other bile acids (Non-Patent Document 1), If this CDCA can be increased, efficient treatment, prevention and amelioration of diseases such as cholesterol and dyslipidemia can be expected.
本発明の目的は、ＣＤＣＡ増加促進用組成物、ＦＸＲの増加促進用組成物及びＦＸＲの活性化促進用組成物を提供することにある。 An object of the present invention is to provide a composition for promoting CDCA increase, a composition for promoting FXR increase, and a composition for promoting FXR activation.
本発明者らは、種々検討した結果、Ｄ－プシコースを含む組成物を動物に継続的に摂取させることにより、糞便中ＣＤＣＡが増加すること、及び肝臓中ＦＸＲが増加することを見出した。 As a result of various investigations, the present inventors found that continuous ingestion of a composition containing D-psicose to animals increases CDCA in feces and FXR in liver.
すなわち、本発明は上記知見に基づき完成されたものであり、以下の［１］～［１１］から構成されるものである。
［１］Ｄ－プシコースを有効成分とする、体内ＣＤＣＡ増加促進用組成物。
［２］Ｄ－プシコースを有効成分とする、体内ＦＸＲ増加促進用又は活性化促進用組成物。
［３］Ｄ－プシコースを有効成分とする、体内ＣＤＣＡ増加促進を介してのＦＸＲ増加促進用又は活性化促進用組成物。
［４］Ｄ－プシコースを１日に１５ｇ以上摂取させるための上記［１］～［３］のいずれかに記載の組成物。
［５］Ｄ－プシコースを少なくとも１４日以上継続して摂取させるための上記［４］に記載の組成物。
［６］Ｄ－プシコースを有効成分とする、ＣＤＣＡ増加促進剤。
［７］Ｄ－プシコースを有効成分とする、ＦＸＲ増加促進又は活性化促進剤。
［８］Ｄ－プシコースを有効成分とする、ＣＤＣＡ増加促進を介してのＦＸＲ増加促進又は活性化促進剤。
［９］Ｄ－プシコースを１日に１５ｇ以上摂取させるための上記［６］～［８］のいずれかに記載の剤。
［１０］Ｄ－プシコースを少なくとも１４日以上継続して摂取させるための上記［９］に記載の剤。
［１１］Ｄ－プシコースを経口摂取することによる、体内のＣＤＣＡ若しくはＦＸＲの増加又はＦＸＲの活性化の促進方法。
That is, the present invention has been completed based on the above findings, and is composed of the following [1] to [11].
[1] A composition for promoting CDCA increase in the body, containing D-psicose as an active ingredient.
[2] A composition for promoting the increase or activation of FXR in the body, containing D-psicose as an active ingredient.
[3] A composition containing D-psicose as an active ingredient for promoting FXR increase or activation via CDCA increase in the body.
[4] The composition according to any one of the above [1] to [3] for ingesting 15 g or more of D-psicose per day.
[5] The composition according to [4] above for allowing D-psicose to be ingested continuously for at least 14 days.
[6] A CDCA increase promoter containing D-psicose as an active ingredient.
[7] FXR increase promoter or activation promoter containing D-psicose as an active ingredient.
[8] An FXR increase promoting or activation promoting agent containing D-psicose as an active ingredient through promoting CDCA increase.
[9] The agent according to any one of [6] to [8] above for ingesting 15 g or more of D-psicose per day.
[10] The agent according to [9] above, for allowing D-psicose to be ingested continuously for at least 14 days.
[11] A method of increasing CDCA or FXR in the body or promoting FXR activation by orally ingesting D-psicose.
本発明のＤ－プシコースを有効成分として含む組成物を摂取すれば、体内のＣＤＣＡを増加させることができ、ひいては、ＦＸＲを増加又は活性化することができる。 By ingesting the composition containing D-psicose of the present invention as an active ingredient, CDCA in the body can be increased, and thus FXR can be increased or activated.
肝臓においてコレステロールから生成される胆汁酸を一次胆汁酸といい、具体的には、コール酸（ＣＡ）及びケノデオキシコール酸（ＣＤＣＡ）をいい、これらのグリシン抱合体（ＧＣＡ及びＧＣＤＣＡ）及びタウリン抱合体（ＴＣＡ及びＴＣＤＣＡ）も含む。これら一次胆汁酸は、腸内に分泌されて腸内細菌に代謝されると、ＣＡはデオキシコール酸（ＤＣＡ）に、ＣＤＣＡはリトコール酸（ＬＣＡ）に変換され、また、ＧＣＤＣＡはウルソデオキシコール酸（ＵＤＣＡ）に、ＴＣＤＣＡはタウロウルソデオキシコール酸（ＴＵＤＣＡ）に変換されて、いわゆる二次胆汁酸となる。 Bile acids produced from cholesterol in the liver are called primary bile acids, specifically cholic acid (CA) and chenodeoxycholic acid (CDCA), and their glycine conjugates (GCA and GCDCA) and taurine conjugates ( TCA and TCDCA). When these primary bile acids are secreted into the intestine and metabolized by intestinal bacteria, CA is converted to deoxycholic acid (DCA), CDCA to lithocholic acid (LCA), and GCDCA to ursodeoxycholic acid. (UDCA), TCDCA is converted to tauroursodeoxycholic acid (TUDCA), a so-called secondary bile acid.
本発明におけるＣＤＣＡの「増加」とは、被験試料摂取後に体内のＣＤＣＡ量が相対的に増加することをいう。具体的には、一定期間の被験試料摂取前後に採取した被験者の糞便又は肝臓中のＣＤＣＡ濃度を液体クロマトグラフ－四重極飛行時間型質量分析装置（以下、「ＬＣ－ＱＴＯＦ／ＭＳ」という。）などにより測定し、その濃度が被験試料摂取前に比して摂取後に上昇した場合をいう。 "Increase" of CDCA in the present invention refers to a relative increase in the amount of CDCA in the body after ingestion of the test sample. Specifically, CDCA concentration in feces or liver of a subject collected before and after ingestion of a test sample for a certain period of time is measured by a liquid chromatograph-quadrupole time-of-flight mass spectrometer (hereinafter referred to as "LC-QTOF/MS"). ), etc., and the concentration increased after ingestion compared to before ingestion of the test sample.
本発明におけるＦＸＲの「増加」とは、被験試料摂取後に体内のＦＸＲ濃度が相対的に増加することをいう。具体的には、一定期間の被験試料摂取前後に採取した被験者の肝臓または肝臓細胞内のＦＸＲ濃度を測定キット、例えば、ＥＬＩＳＡ Ｋｉｔ ｆｏｒ ＦａｒｎｅｓｏｉｄＸ Ｒｅｃｅｐｔｏｒ （ＦＸＲ）（Ｃｌｏｕｄ－Ｃｌｏｎｅ社製）などを用いて測定し、その濃度が被験試料摂取前に比して増加した場合をいう。 "Increase" of FXR in the present invention refers to a relative increase in FXR concentration in the body after ingestion of the test sample. Specifically, the FXR concentration in the liver or liver cells of the subject collected before and after ingestion of the test sample for a certain period of time is measured using a kit such as ELISA Kit for FarnesoidX Receptor (FXR) (manufactured by Cloud-Clone). It refers to the case where the measured concentration increases compared to before ingestion of the test sample.
本発明におけるＦＸＲの「活性化」とは、被験試料摂取後に体内ＣＤＣＡ量が増加すればＦＸＲに対する結合量は多くなり、最終的にＦＸＲが活性化されることになるので、体内ＣＤＣＡ量の増加により推定される効果をいう。 "Activation" of FXR in the present invention means that if the amount of CDCA in the body increases after ingestion of the test sample, the amount of binding to FXR increases, and FXR is finally activated, so the amount of CDCA in the body increases. It refers to the effect estimated by
本発明におけるＤ－プシコースは、もっとも簡便には、Ｄ－フラクトースを原料に酵素（エピメラーゼ）によって生産されるが、酵素的に生産されたものに限らず、化学的に生産されたものでもよい。 D-psicose in the present invention is most conveniently produced by an enzyme (epimerase) using D-fructose as a starting material, but it is not limited to enzymatic production, and may be chemical production.
本発明の有効成分であるＤ－プシコースの摂取量は、少なくとも一日あたり０．０８ｇ／ｋｇ体重が必要であり、好ましくは０．０８ｇ～０．８ｇ／ｋｇ体重、より好ましくは０．１～０．５ｇ/ｋｇ体重、さらに好ましくは０．１～０．３ｇ／ｋｇ体重である。また、本発明の有効成分としてのＤ－プシコースの摂取方法は、経腸摂取及び経口摂取のいずれでも構わないが、経口摂取がより好ましい。したがって、本発明の組成物又は剤におけるＤ－プシコースの含量は、その目的、用途、形態、剤型、症状、体重等に応じて任意に定めることになるので、特に限定されるものではないが、食品組成物として摂取する場合は、その組成物中におけるＤ－プシコースの含量は１～１００質量％とするのがよく、好ましくは１０～９０質量％、より好ましくは３０～８０質量％とするのがよい。また、剤の場合、摂取の利便性を考慮すれば、５０～１００質量％とするのがよく、より好ましくは７０～９５質量％とするのがよい。標準的な成人（体重６０ｋｇを想定）であれば、一日当たり少なくとも５ｇ、好ましくは１０ｇ、より好ましくは１５ｇであるので、本発明の組成物又は剤は、当該用量を摂取できるよう設計されるのがよい。 The intake of D-psicose, which is the active ingredient of the present invention, should be at least 0.08 g/kg body weight per day, preferably 0.08 to 0.8 g/kg body weight, more preferably 0.1 to 0.1 g/kg body weight. 0.5 g/kg body weight, more preferably 0.1 to 0.3 g/kg body weight. D-psicose as an active ingredient of the present invention may be ingested either enterally or orally, but oral ingestion is more preferred. Therefore, the content of D-psicose in the composition or agent of the present invention is arbitrarily determined according to its purpose, application, form, dosage form, symptoms, body weight, etc., and is not particularly limited. When ingested as a food composition, the content of D-psicose in the composition is preferably 1 to 100% by mass, preferably 10 to 90% by mass, more preferably 30 to 80% by mass. It's good. In the case of a drug, it is preferably 50 to 100% by mass, more preferably 70 to 95% by mass, considering the convenience of ingestion. A normal adult (assuming a body weight of 60 kg) is at least 5 g, preferably 10 g, and more preferably 15 g per day, so the composition or agent of the present invention is designed so that this dose can be taken. is good.
本発明における組成物又は剤の摂取期間は、少なくとも１４日以上であり、好ましくは３０日以上である。 The intake period of the composition or agent in the present invention is at least 14 days or more, preferably 30 days or more.
本発明における組成物又は剤の形状は、特に限定されないが、例えば、水溶液、錠剤、顆粒等の形状により摂取することが可能である。また、摂取タイミングは、食事前、食事中、食事後のいずれでも構わないが、食事前又は食事中が好ましく、食事前であることがより好ましい。 The form of the composition or agent in the present invention is not particularly limited, but it can be ingested in the form of, for example, an aqueous solution, tablets, granules, and the like. The timing of ingestion may be before, during, or after a meal, preferably before or during a meal, and more preferably before a meal.
本発明における組成物又は剤は、飲食品に配合することもできる。例えば、ベーカリー、麺、お好み焼き、たこ焼き、ホットケーキ、バッター等の穀類を主成分とする製品やそれら製造のためのミックス粉、和菓子、水練り製品、畜肉製品、米飯加工品のほか、ヨーグルト、プリン、ゼリー、アイスクリームなどのデザート類、マヨネーズやソースを含むたれ・ドレッシング類、あんかけ類、嚥下剤、又は粉末飲料、清涼飲料、炭酸飲料などのドリンク類などへの配合が例示されるが、これらに特に限定されるものではない。 The composition or agent of the present invention can also be incorporated into food and drink. For example, bakery products, noodles, okonomiyaki, takoyaki, pancakes, batter, and other grain-based products, mixed powders for their production, Japanese sweets, water paste products, livestock meat products, processed rice products, yogurt, pudding, Desserts such as jelly and ice cream, sauces and dressings containing mayonnaise and sauces, sauces, swallowing agents, or drinks such as powdered drinks, soft drinks, and carbonated drinks. It is not particularly limited.
以下、実施例により本発明を具体的に説明するが、これらによって本発明が限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these.
（ヒトにおけるＤ－プシコース継続摂取試験）
（１）被験者
被験者は２５歳以上６３歳以下の男性であって、高コレステロール血症の未治療者（１２０ｍｇ／ｄｌ≦空腹時ＬＤＬ－Ｃ＜１６０ｍｇ／ｄｌ：７名）及びＬＤＬコレステロール値の上昇が予想される糖尿病境界型の未治療者（１１０ｍｇ／ｄｌ≦空腹時血糖値＜１２６ｍｇ／ｄｌ、又は６．２≦ＨｂＡ１ｃ（ＮＧＳＰ）＜６．５：７名）を選定した。
（２）試験方法
試験方法は、非盲検試験（オープンテストともいう）にて行った。
（３）被験食品
被検食品は、Ｄ－プシコース１５ｇを１日１回とし、水などと共に摂取した。なお、摂取する時間帯は特に限定せず、食前や食後などいずれでもよいとした。
（４）便検体の採取
上記被験者を７名ずつ、事前検査における高コレステロール血症の未治療者及び糖尿病境界型の未治療者の２群（Ａ群、Ｂ群）に割付け、各群に被験食品を１日１回摂取させた。全摂取期間は４週間（２８日間）とし、摂取期間開始前５日間以内及び摂取期間終了後５日間以内にそれぞれ１回、糞便を採取した。採取した各被験者の糞便は、胆汁酸濃度の測定に用いた。
(D-psicose continuous intake test in humans)
(1) Subjects The subjects were males aged 25 to 63 years old who had never been treated for hypercholesterolemia (120 mg/dl ≤ fasting LDL-C < 160 mg/dl: 7 subjects) and elevated LDL cholesterol levels. Pre-treatment borderline diabetes mellitus (110 mg/dl ≤ fasting blood glucose level < 126 mg/dl, or 6.2 ≤ HbA1c (NGSP) < 6.5: 7) were selected.
(2) Test method The test method was an open-label test (also called an open test).
(3) Test food As the test food, 15 g of D-psicose was taken once a day with water. In addition, the timing of ingestion is not particularly limited, and may be before or after meals.
(4) Collection of stool specimens Each of the above seven subjects was assigned to two groups (groups A and B) of untreated hypercholesterolemia and untreated borderline diabetes in the preliminary examination, and each group was tested. Food was taken once a day. The total ingestion period was 4 weeks (28 days), and feces were collected once each within 5 days before the ingestion period started and within 5 days after the ingestion period ended. The feces collected from each subject were used to measure bile acid concentrations.
（胆汁酸の測定及び結果）
各被験者から採取した糞便（以下、「試料」という。）を、ビーズチューブに１００ｍｇ精秤し、９倍量の酢酸ナトリウムバッファー／エタノール混合溶液を加えて試料を破砕した後、８５℃、３０ｍｉｎにて熱処理を行った。遠心分離機で遠心後（１４０００ｒｐｍ、１０ｍｉｎ）、その上清を超純水（ＭｉｌｌｉＱ）で４倍希釈し、Ｂｏｎｄ Ｅｌｕｔｅ Ｃ１８カートリッジ（アジレント・テクノロジー社製）に供し固相抽出を行った。得られた抽出液は蒸発乾固後に、５０％エタノールに溶解し、孔径０．２μｍの親水性ＰＴＦＥフィルターでろ過し、ろ過後の抽出液に内部標準液（ｄ４－コール酸：Ｃ２４Ｈ３６Ｄ４Ｏ５）を加えて試料溶液とした。その試料溶液を用いて、ＬＣ－ＱＴＯＦ／ＭＳにより胆汁酸濃度の測定を行った。測定対象は、表１に示す一次胆汁酸及び二次胆汁酸の全成分とし、分析条件及び測定条件は、以下の表２及び表３に示した。
(Measurement and results of bile acid)
100 mg of stool collected from each subject (hereinafter referred to as "sample") was accurately weighed into a bead tube, 9 times the amount of sodium acetate buffer / ethanol mixed solution was added to crush the sample, and then heated at 85 ° C. for 30 minutes. heat treatment was performed. After centrifugation with a centrifuge (14000 rpm, 10 min), the supernatant was diluted 4-fold with ultrapure water (MilliQ) and applied to a Bond Elute C18 cartridge (manufactured by Agilent Technologies) for solid phase extraction. The resulting extract was evaporated to dryness, dissolved in 50% ethanol, filtered through a hydrophilic PTFE filter with a pore size of 0.2 μm, and an internal standard solution (d4-cholic acid: C 24 H 36 D 4 O 5 ) was added to obtain a sample solution. Using the sample solution, the bile acid concentration was measured by LC-QTOF/MS. All components of the primary bile acids and secondary bile acids shown in Table 1 were measured, and the analysis conditions and measurement conditions are shown in Tables 2 and 3 below.
上述の手順により測定した各胆汁酸の濃度（μｍｏｌ／ｇ試料）のうち、全被験者（１４名）のＣＤＣＡ濃度の平均値を算出した。結果を表４に示す。 Among the concentrations of each bile acid (μmol/g sample) measured by the above procedure, the average CDCA concentration of all subjects (14 persons) was calculated. Table 4 shows the results.
ＣＤＣＡ濃度は、Ｄ－プシコース摂取前と比較して、Ｄ－プシコース摂取後に上昇する傾向を示した。 The CDCA concentration tended to increase after D-psicose ingestion compared to before D-psicose ingestion.
（ラットの飼育１）
次に、Ｄ－プシコース摂取による体内のＦＸＲ濃度の変動を確認するため、ラットで試験を行った。５週齢の雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙラット（以下、「ＳＤラット」という。）１２匹を、コントロール摂取群及び３％Ｄ－プシコース摂取群の２群（１群あたり５匹又は６匹）に分け、被験飼料と水を自由摂取として２週間飼育した。与えた餌の組成を表５に示す。
(Rat rearing 1)
Next, in order to confirm changes in FXR concentration in the body due to ingestion of D-psicose, a test was conducted in rats. Twelve 5-week-old male Sprague-Dawley rats (hereinafter referred to as "SD rats") were divided into two groups (5 or 6 rats per group), a control intake group and a 3% D-psicose intake group, The rats were fed with test feed and water ad libitum for 2 weeks. Table 5 shows the composition of the food given.
（ラット肝臓内タンパク質の抽出）
飼育したＳＤラットを解剖して肝臓を摘出し、市販のタンパク抽出キット（Ｍｉｎｕｔｅ Ｔｏｔａｌ Ｐｒｏｔｅｉｎ Ｅｘｔｒａｃｔｉｏｎ Ｋｉｔ：インヴェント バイオテクノロジー社製）を用いてタンパク質を抽出した。
(Extraction of protein in rat liver)
The raised SD rats were dissected to extract the liver, and protein was extracted using a commercially available protein extraction kit (Minute Total Protein Extraction Kit: manufactured by Invent Biotechnology).
（ラット肝臓内ＦＸＲ濃度の測定及び結果）
抽出したタンパク質について、市販キット（ＥＬＩＳＡ Ｋｉｔ ｆｏｒ Ｆａｒｎｅｓｏｉｄ Ｘ Ｒｅｃｅｐｔｏｒ （ＦＸＲ）：Ｃｌｏｕｄ－Ｃｌｏｎｅ社製）を用いてＦＸＲ濃度（μｇ／ｇ肝臓）を測定し、摂取群ごとの平均値を算出した。その結果を表６に示す。
(Measurement and results of FXR concentration in rat liver)
For the extracted protein, the FXR concentration (μg/g liver) was measured using a commercially available kit (ELISA Kit for Farnesoid X Receptor (FXR): manufactured by Cloud-Clone), and the average value for each intake group was calculated. Table 6 shows the results.
Ｄ－プシコース３％摂取群では、コントロール摂取群と比較して、肝臓ＦＸＲ濃度が上昇傾向を示した。 In the D-psicose 3% intake group, the hepatic FXR concentration tended to increase compared to the control intake group.
なお、飼育したＳＤラットは、一日当たり平均１３５ｋｃａｌ／ｋｇ体重の餌を摂取しており、その一日当たりの摂取エネルギーは、ヒト（体重６０ｋｇ）の約９．５倍と算出された。飼育したＳＤラットは、一日当たり平均２．５ｇ／ｋｇ体重のＤ－プシコースを摂取しており、これは、ヒト（体重６０ｋｇ）がＤ－プシコースを１５ｇ／日摂取した場合の摂取量（０．２５ｇ／ｋｇ体重）の１０倍である。よって、飼育したＳＤラットのＤ－プシコース摂取量は、前述のヒト試験におけるＤ－プシコース摂取量と同等であったといえる。 It should be noted that the SD rats ingested an average of 135 kcal/kg body weight per day, and the energy intake per day was calculated to be about 9.5 times that of humans (60 kg body weight). Raised SD rats ingested an average of 2.5 g/kg body weight of D-psicose per day, which is equivalent to the intake of 15 g/day of D-psicose in humans (60 kg body weight) (0.5 g/day). 25 g/kg body weight). Therefore, it can be said that the D-psicose intake of the bred SD rats was equivalent to the D-psicose intake in the human test described above.
（ラットの飼育２）
上述のラット試験においては、解剖前までに絶食期間を設けなかった。そこて、より正確な数値を確認するために、新たにラットを飼育し、その肝細胞を分離後、ＦＸＲ濃度の測定をすることとした。
(Rat rearing 2)
In the rat study described above, there was no fasting period before necropsy. Therefore, in order to confirm a more accurate value, rats were newly bred, and the FXR concentration was measured after separating the hepatocytes.
まず、７週齢の雄性ＳＤラット６匹を、コントロール摂取群及び３％Ｄ－プシコース摂取群の２群（１群あたり３匹）に分け、被験飼料と水を自由摂取として２週間飼育した。なお、与えた餌の組成は表５と同じである。 First, 6 7-week-old male SD rats were divided into 2 groups (3 rats per group), a control group and a 3% D-psicose group, and fed for 2 weeks with test feed and water ad libitum. The composition of the food given was the same as in Table 5.
（ラット肝細胞の培養及びタンパク質抽出）
飼育後のＳＤラットを解剖し、肝細胞を分離した。分離した各肝細胞は、ウィリアムＥ培地で４８時間培養した。その後、市販キット（Ｍｉｎｕｔｅ Ｔｏｔａｌ Ｐｒｏｔｅｉｎ Ｅｘｔｒａｃｔｉｏｎ Ｋｉｔ：インヴェント バイオテクノロジー社製）を用いて、培養した肝細胞からタンパク質を抽出した。
(Culturing and protein extraction of rat hepatocytes)
After breeding, SD rats were dissected and hepatocytes were separated. Each isolated hepatocyte was cultured in William's E medium for 48 hours. Thereafter, proteins were extracted from the cultured hepatocytes using a commercially available kit (Minute Total Protein Extraction Kit: manufactured by Invent Biotechnology).
（ラット肝細胞内ＦＸＲ濃度の測定及び結果）
抽出したタンパク質について、市販キット（ＥＬＩＳＡ Ｋｉｔ ｆｏｒ ＦａｒｎｅｓｏｉｄＸ Ｒｅｃｅｐｔｏｒ （ＦＸＲ）：Ｃｌｏｕｄ－Ｃｌｏｎｅ社製）を用いてＦＸＲ濃度を測定し、摂取群ごとの平均値を算出した。その結果を表７に示す。
(Measurement and results of FXR concentration in rat hepatocytes)
For the extracted protein, the FXR concentration was measured using a commercially available kit (ELISA Kit for FarnesoidX Receptor (FXR): manufactured by Cloud-Clone), and the average value for each ingestion group was calculated. Table 7 shows the results.
その結果、Ｄ－プシコースを摂取することにより、肝細胞のＦＸＲ濃度が上昇することがわかった。 As a result, it was found that ingestion of D-psicose increased FXR concentration in hepatocytes.
以上より、Ｄ－プシコースは、体内のＣＤＣＡとＦＸＲを増加させるので、Ｄ－プシコースを有効成分とする体内ＣＤＣＡ増加促進用組成物、ＦＸＲ増加促進用組成物又はＦＸＲ活性化促進用組成物を提供することができる。 As described above, since D-psicose increases CDCA and FXR in the body, a composition for promoting CDCA increase in the body, a composition for promoting an increase in FXR, or a composition for promoting FXR activation containing D-psicose as an active ingredient is provided. can do.
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| WO2005115409A1 (en) | 2004-05-26 | 2005-12-08 | National University Corporation Kagawa University | Composition for inhibiting the onset of arteriosclerosis and inhibition method |
| JP2010018528A (en) | 2008-07-09 | 2010-01-28 | Matsutani Chem Ind Ltd | Biological function improving composition comprising dietary fiber and rare sugar |
| WO2013035479A1 (en) | 2011-09-06 | 2013-03-14 | 合同会社希少糖食品 | Composition for improving in vivo metabolism parameter |
| JP2018530600A (en) | 2015-09-01 | 2018-10-18 | シージェイ チェルジェダン コーポレイション | Lipid absorption inhibition and / or elimination promotion method using D-psicose |
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| WO2005115409A1 (en) | 2004-05-26 | 2005-12-08 | National University Corporation Kagawa University | Composition for inhibiting the onset of arteriosclerosis and inhibition method |
| JP2010018528A (en) | 2008-07-09 | 2010-01-28 | Matsutani Chem Ind Ltd | Biological function improving composition comprising dietary fiber and rare sugar |
| WO2013035479A1 (en) | 2011-09-06 | 2013-03-14 | 合同会社希少糖食品 | Composition for improving in vivo metabolism parameter |
| JP2018530600A (en) | 2015-09-01 | 2018-10-18 | シージェイ チェルジェダン コーポレイション | Lipid absorption inhibition and / or elimination promotion method using D-psicose |
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