JPWO2008032450A1 - Preventive and / or therapeutic agent for fatty liver - Google Patents
Preventive and / or therapeutic agent for fatty liver Download PDFInfo
- Publication number
- JPWO2008032450A1 JPWO2008032450A1 JP2008534244A JP2008534244A JPWO2008032450A1 JP WO2008032450 A1 JPWO2008032450 A1 JP WO2008032450A1 JP 2008534244 A JP2008534244 A JP 2008534244A JP 2008534244 A JP2008534244 A JP 2008534244A JP WO2008032450 A1 JPWO2008032450 A1 JP WO2008032450A1
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- Prior art keywords
- natriuretic peptide
- fatty liver
- therapeutic agent
- prophylactic
- agonist
- Prior art date
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Abstract
本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する脂肪肝予防剤および／または治療剤に関する。本発明の医薬は、脂肪肝を予防・治療できるだけでなく、肥満や糖尿病などに代表されるメタボリックシンドロームも予防できる。The present invention relates to an agent for preventing and / or treating fatty liver containing an agonist of natriuretic peptide receptor GC-A. The medicament of the present invention not only can prevent and treat fatty liver, but can also prevent metabolic syndrome represented by obesity and diabetes.
Description
本発明は、脂肪肝の予防剤および／または治療剤に関する。 The present invention relates to a prophylactic and / or therapeutic agent for fatty liver.
健康診断で異常検査所見とされる項目の中で、肝機能障害は高脂血症に次いで多く、その肝機能障害の大部分は脂肪肝となっている。脂肪肝とは、肝細胞内に中性脂肪を主とした脂質が貯留して重量比で５％以上となった状態である。なお、中性脂肪とは、グリセリンの脂肪酸エステル（トリアシルグリセロール）である。脂質が５％以上となると、肝小葉の肝細胞（肝実質細胞）の３分の１以上に脂肪滴が現れる。脂肪肝の原因としては、飲酒、肥満、糖尿病、薬物など様々なものがあるが、その成因によりアルコール性脂肪肝と非アルコール性脂肪肝に大別されている。非アルコール性脂肪肝は、糖尿病、高脂血症、肥満等の生活習慣病の増加に伴い増加している。 Among the items that are regarded as abnormal test findings in medical examinations, liver dysfunction is the second most common after hyperlipidemia, and most of the liver dysfunction is fatty liver. Fatty liver is a state in which lipids mainly composed of neutral fat are stored in hepatocytes and the weight ratio is 5% or more. Neutral fat is a fatty acid ester of glycerin (triacylglycerol). When the lipid is 5% or more, lipid droplets appear in more than one third of the hepatocytes (liver parenchymal cells) of the liver lobule. There are various causes of fatty liver, such as alcohol consumption, obesity, diabetes, drugs, and the like, which are roughly classified into alcoholic fatty liver and non-alcoholic fatty liver. Non-alcoholic fatty liver is increasing with an increase in lifestyle-related diseases such as diabetes, hyperlipidemia and obesity.
アルコール性脂肪肝は、肝炎、肝硬変、肝臓癌へと進行する可能性が高く、その治療法としては禁酒を中心としたものとなる。一方、非アルコール性脂肪肝（ｎｏｎａｌｃｏｌｉｃ ｆａｔｔｙ ｌｉｖｅｒ ｄｉｓｅａｓｅ：ＮＡＦＬＤ）は、従来、食事療法や運動療法で改善され特に重篤な疾患へ移行することのない可逆的なものが多いとされてきたが、近年、治療せず放置すると肝機能が低下し、肝硬変などへ進展する危険性もあることが指摘されている。とりわけ、ＮＡＦＬＤのうち、炎症を伴う非アルコール性脂肪性肝炎（ｎｏｎａｌｃｏｌｉｃ ｓｔｅａｔｏｈｅｐａｔｉｔｉｓ：ＮＡＳＨ）は、肝組織学的にアルコール性肝炎に類似した炎症を認め、肝硬変から肝細胞癌へ進行する危険性が高い疾患であることがわかってきている。したがって、これまでに増して、ＮＡＦＬＤ、特に、ＮＡＳＨを適切に治療することは医療上非常に重要な課題であると考えられている。 Alcoholic fatty liver is likely to progress to hepatitis, cirrhosis, and liver cancer, and its treatment is centered on alcohol cessation. On the other hand, nonalcoholic fatty liver disease (NAFLD) has been considered to be reversible, which is improved by diet and exercise therapy and does not shift to a particularly serious disease. In recent years, it has been pointed out that if left untreated, the liver function is lowered and there is a risk of progressing to cirrhosis. In particular, among non-alcoholic steatohepatitis (NASH) with inflammation, NAFLD has inflammation similar to alcoholic hepatitis in liver histology, and has a high risk of progression from cirrhosis to hepatocellular carcinoma It has become known to be a disease. Therefore, more than ever, appropriate treatment of NAFLD, particularly NASH, is considered to be a very important medical issue.
一方、メタボリックシンドロームは、内臓脂肪（腹腔内脂肪）の蓄積に加え、インスリン抵抗性、脂質異常、高血圧等の心血管病に対する複数のリスクが合併した症候群であり、過栄養を基礎とした内臓脂肪の蓄積がもたらす種々の生活習慣病につながる病態であると理解されている。メタボリックシンドロームの患者においては、非メタボリックシンドローム患者と比較して高頻度でＮＡＳＨを含むＮＡＦＬＤが観察され、多くの患者がＮＡＳＨを含むＮＡＦＬＤを併発していることが知られている。 Metabolic syndrome, on the other hand, is a syndrome that is associated with the accumulation of visceral fat (intraperitoneal fat) and multiple risks for cardiovascular diseases such as insulin resistance, dyslipidemia, and hypertension. It is understood that this is a pathological condition that leads to various lifestyle-related diseases brought about by the accumulation of. In patients with metabolic syndrome, NAFLD containing NASH is observed more frequently than patients with non-metabolic syndrome, and it is known that many patients have concurrent NAFLD containing NASH.
すなわち、非アルコール性脂肪肝の患者は、肥満、高血圧、糖尿病や高脂血症などの基礎疾患を併発したメタボリックシンドロームを伴う場合があり、このような患者においては、脂肪肝の治療のみではなく、それらの基礎疾患の治療も必要となる場合がある。したがって、脂肪肝の治療には、このような基礎疾患に悪影響を及ぼすことがない薬物、さらにはこれらの基礎疾患を同時に治療し得る薬物を使用することが望ましい。 That is, patients with non-alcoholic fatty liver disease may have metabolic syndrome associated with basic diseases such as obesity, hypertension, diabetes and hyperlipidemia. In such patients, not only treatment of fatty liver Treatment of those underlying diseases may also be necessary. Therefore, for the treatment of fatty liver, it is desirable to use drugs that do not adversely affect such underlying diseases, and further drugs that can simultaneously treat these underlying diseases.
脂肪肝の食事療法としては、飲酒制限、カロリー制限および低脂肪・高蛋白食の摂取が中心であり、運動療法としては、有酸素運動などにより脂肪をエネルギーとして消費する方策が取られる。その際、脂肪肝は拒食症などの栄養障害でも引き起こされることが知られているように、極端な食事制限を行うと筋肉を落として逆に脂肪を増やすことから急激な体重減少は好ましくなく、１〜２ｋｇ／月程度の減量が望ましい。このように、脂肪肝の治療はコントロールされた食事とかなりの長時間の有酸素運動による根気の必要なものとなる。 As dietary therapy for fatty liver, alcohol consumption restriction, caloric restriction, and intake of low-fat / high-protein diet are mainly used. As exercise therapy, measures are taken to consume fat as energy by aerobic exercise or the like. At that time, as it is known that fatty liver is also caused by malnutrition such as anorexia, sudden weight loss is not preferable because extreme muscle restriction drops muscles and increases fat on the contrary, A weight loss of about 1-2 kg / month is desirable. Thus, the treatment of fatty liver requires a controlled diet and perseverance with a considerable length of aerobic exercise.
現代人の生活は、ストレスと飽食に満ちたものとなっており、脂肪肝を引き起こしやすい状況となっていることから、上記のような根気の要る脂肪肝の治療法に代わって、あるいはそれと併用することのできる新たな治療法が望まれる。 Because modern life is full of stress and satiety, and is prone to causing fatty liver, it can be used instead of, or in addition to, the above-mentioned persistent treatment of fatty liver. New therapies that can be used in combination are desired.
ところで、肥満や高血圧の患者においては、心臓や腎臓などの循環器系器官に過度な負担がかかっている。そのような状況においては、ナトリウム利尿ペプチドと称されるペプチドの産生・分泌が亢進し、循環器系器官への負担を和らげる代償作用が働いていることはよく知られている。ナトリウム利尿ペプチドと称されるペプチドには、心房性ナトリウム利尿ペプチド（ＡＮＰ）、脳性ナトリウム利尿ペプチド（ＢＮＰ）およびＣ型ナトリウム利尿ペプチド（ＣＮＰ）が知られている。ＡＮＰは、心房細胞で産生され分泌されるアミノ酸２８個から成る環状構造を有するペプチドであり、腎臓では利尿作用を示し、血管では血管平滑筋を弛緩・拡張する。ＡＮＰは、さらにレニン・バソプレシン・アルドステロン系に対して拮抗的に作用する。これらの作用は、総合的に血圧の低下や体液量の低減などを通じて心臓の負担を軽減する方向に働く。ＢＮＰは、アミノ酸３２個から成る環状構造を有するペプチドであり、主に心室細胞で産生され分泌されてＡＮＰと同様な作用を有する。ＡＮＰとＢＮＰは、ともにグアニレートシクラーゼドメインを有する受容体ＮＰＲ−Ａ（別名、ＧＣ−Ａ）に結合して、ｃＧＭＰの産生を促進して上記の作用を発現する。実際、ＡＮＰはうっ血性心不全などにおいて心房膨満圧の上昇に伴い分泌が促進され、上記の作用によりうっ血性心不全などの症状を軽減する働きをしている。ＢＮＰも心筋梗塞などの際に、分泌が促進され、上記の作用により心筋梗塞などに伴う諸症状を和らげる働きをしている（非特許文献１）。 By the way, in patients with obesity and hypertension, an excessive burden is placed on circulatory organs such as the heart and kidneys. In such a situation, it is well known that the production and secretion of a peptide called a natriuretic peptide is enhanced, and a compensatory action that reduces the burden on the circulatory system organ is working. As peptides called natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are known. ANP is a peptide having a cyclic structure consisting of 28 amino acids produced and secreted by atrial cells, exhibits diuretic action in the kidney, and relaxes / expands vascular smooth muscle in blood vessels. ANP also acts antagonistically on the renin-vasopressin-aldosterone system. These actions generally work to reduce the burden on the heart through a reduction in blood pressure and a reduction in the amount of body fluid. BNP is a peptide having a cyclic structure consisting of 32 amino acids, and is produced and secreted mainly by ventricular cells and has the same action as ANP. Both ANP and BNP bind to the receptor NPR-A (also known as GC-A) having a guanylate cyclase domain, and promote the production of cGMP to express the above action. In fact, ANP promotes secretion with increasing atrial fullness pressure in congestive heart failure or the like, and functions to reduce symptoms such as congestive heart failure by the above action. BNP also promotes secretion during myocardial infarction, and functions to relieve various symptoms associated with myocardial infarction by the above-described action (Non-patent Document 1).
最近になって、脂肪組織においてもナトリウム利尿ペプチド受容体ＧＣ−Ａの発現が確認されて、ＡＮＰやＢＮＰは心血管系に作用するばかりではなく、脂肪分解の促進にも関与しているという報告がある（非特許文献２）。ＡＮＰやＢＮＰの脂肪分解促進作用は、ナトリウム利尿ペプチド受容体ＧＣ−Ａの細胞内部分に存在するグアニレートシクラーゼにより産生されたｃＧＭＰがｃＧＭＰ依存性のプロテインカイネースＩ（ｃＧＫＩ）に作用し、ホルモン感受性リパーゼのリン酸化を促進して活性化することによると考えられている。活性化されたホルモン感受性リパーゼは、トリグリセリドを遊離脂肪酸に加水分解する。しかしながら、上記のような脂肪組織に対するナトリウム利尿ペプチドの作用は若年男子における肥満には関与していないことが報告されている（非特許文献３）。また、ＡＮＰやＢＮＰ等のナトリウム利尿ペプチドによる脂肪組織における脂肪分解の促進作用が肝細胞にどのような影響を及ぼすかについては知られていない。すなわち、脂肪組織とは本質的に異なる肝細胞においてＡＮＰやＢＮＰ等のナトリウム利尿ペプチドが脂肪の蓄積や代謝に直接的にまたは間接的に及ぼす作用については何ら明らかにされていない。実際、最近のナトリウム利尿ペプチドに関する総説においても、心血管系疾患への治療上の応用に関しては詳細に記載されているが、脂肪肝の予防および／または治療への応用については何ら示唆されていない（非特許文献４）。
本発明においては、脂肪肝の予防および／または治療に有用な薬剤を見出すことが課題である。さらには、心筋梗塞などの心血管系の疾患を引き起こす可能性が高いメタボリックシンドロームの患者において、脂肪肝の予防および／または治療に有用な薬剤を見出すことが課題である。 An object of the present invention is to find a drug useful for the prevention and / or treatment of fatty liver. Furthermore, it is a problem to find a drug useful for the prevention and / or treatment of fatty liver in patients with metabolic syndrome who are likely to cause cardiovascular diseases such as myocardial infarction.
本発明者等は、脂肪肝を予防および／または治療することができる薬剤について、さらには心筋梗塞などの心血管系の疾患を引き起こす可能性が高いメタボリックシンドロームに伴う脂肪肝（または、メタボリックシンドロームを伴う脂肪肝）を予防および／または治療することができる薬剤について鋭意検討した結果、ナトリウム利尿ペプチドが体重減少、内臓脂肪の減少、耐糖能の改善、および脂肪肝の抑制作用を有することを見出した。さらには、ｃＧＭＰ依存性のプロテインカイネースＩ（ｃＧＫＩ）の活性化により、ナトリウム利尿ペプチドと同様に、体重減少、内臓脂肪の減少、耐糖能の改善、および脂肪肝の抑制作用を有することを見出して、本発明を完成した。 The inventors of the present invention have proposed an agent capable of preventing and / or treating fatty liver, as well as fatty liver (or metabolic syndrome associated with metabolic syndrome that is likely to cause cardiovascular diseases such as myocardial infarction). As a result of intensive studies on drugs capable of preventing and / or treating (hepatic steatosis), it was found that natriuretic peptides have weight loss, visceral fat reduction, improved glucose tolerance, and fatty liver suppression. . Furthermore, it has been found that activation of cGMP-dependent protein kinase I (cGKI) has the effects of reducing body weight, reducing visceral fat, improving glucose tolerance, and inhibiting fatty liver, similar to natriuretic peptide. Thus, the present invention has been completed.
具体的には、ＢＮＰを連続投与した状況に擬して、肝臓特異的にＢＮＰを過剰発現させたマウス（以下、ＢＮＰ−Ｔｇマウス）を作製し、高脂肪食を与えてＢＮＰの効果を検討した結果、野生型のマウスに比してＢＮＰ−Ｔｇマウスでは体重増加、内臓脂肪の増加、肝重量増加、および肝の中性脂肪増加が有意に抑制されることを見出した。また、高脂肪食を与えたＢＮＰ−Ｔｇマウスにおいて、糖負荷やインスリン投与時に野生型のマウスに比して血糖値の上昇が有意に軽減されることから、ナトリウム利尿ペプチドが耐糖能やインスリン感受性も改善させることを見出した。 Specifically, a mouse that overexpressed BNP in a liver-specific manner (hereinafter referred to as a BNP-Tg mouse) was produced in a manner similar to the situation where BNP was continuously administered, and the effect of BNP was examined by giving a high fat diet. As a result, it was found that body weight gain, visceral fat increase, liver weight increase, and hepatic neutral fat increase were significantly suppressed in BNP-Tg mice compared to wild-type mice. In addition, in BNP-Tg mice fed with a high fat diet, the increase in blood glucose level is significantly reduced compared to wild-type mice during glucose tolerance and insulin administration, so that the natriuretic peptide is glucose tolerance and insulin sensitivity. Also found to improve.
さらには、ナトリウム利尿ペプチドがナトリウム利尿ペプチド受容体ＧＣ−Ａに作用して産生されるｃＧＭＰにより活性化されるｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）を全身性に過剰発現させたマウス（以下、ｃＧＫ−Ｔｇマウス）に高脂肪食を与えた結果、ＢＮＰ−Ｔｇマウスにおけると同様に、野生型のマウスに比して体重増加、内臓脂肪の増加、肝重量増加、および肝の中性脂肪増加が有意に抑制されることを見出した。また、高脂肪食を与えたｃＧＫ−Ｔｇマウスにおいて、糖負荷やインスリン投与時に野生型のマウスに比して血糖値の上昇が有意に軽減されることから、ｃＧＫＩの活性化が耐糖能やインスリン感受性も改善させることを見出した。また、ＧＣ−Ａヘテロノックアウトマウスに高脂肪食を与えた結果、野生型のマウスに比して肥満、脂肪肝形成が大きく、耐糖能障害の程度も大きいことを見出した。 Furthermore, mice overexpressing cGMP-dependent protein kinase I (cGKI) activated by cGMP produced by the action of natriuretic peptide on natriuretic peptide receptor GC-A (hereinafter referred to as “systemic overexpression”). (cGK-Tg mice) were fed a high fat diet, resulting in increased body weight, increased visceral fat, increased liver weight, and increased neutral fat in the liver, as in BNP-Tg mice. Was found to be significantly suppressed. Moreover, in cGK-Tg mice fed with a high fat diet, the increase in blood glucose level is significantly reduced compared to wild-type mice during glucose tolerance and insulin administration. It has been found that sensitivity is also improved. In addition, as a result of giving a high fat diet to GC-A hetero knockout mice, it was found that obesity and fatty liver formation were greater and the degree of impaired glucose tolerance was greater than in wild type mice.
これらの結果は、ＢＮＰ等のナトリウム利尿ペプチドを投与することにより、脂肪肝を予防および／または治療できることを示すばかりではなく、肥満や糖尿病などに代表されるメタボリックシンドロームに伴う脂肪肝（または、肥満や糖尿病などに代表されるメタボリックシンドロームを伴う脂肪肝）を予防および／または治療できることを示す。さらに、メタボリックシンドロームや肥満を予防および／または治療できることを示す。さらに、たとえばＡＮＰのようにＢＮＰ同様ＧＣ−Ａのアゴニストとして機能することが知られている化合物に、ＢＮＰと同様の効果があることを示していると考える。同様に、ｃＧＫＩが活性化されることにより脂肪肝を予防および／または治療できることを示すばかりではなく、肥満や糖尿病などに代表されるメタボリックシンドロームに伴う脂肪肝（または、肥満や糖尿病などに代表されるメタボリックシンドロームを伴う脂肪肝）を予防および／または治療できることを示す。さらに、メタボリックシンドロームや肥満を予防できることを示す。 These results not only indicate that administration of a natriuretic peptide such as BNP can prevent and / or treat fatty liver, but also fatty liver (or obesity associated with metabolic syndrome such as obesity and diabetes). Or fatty liver with metabolic syndrome represented by diabetes, etc. can be prevented and / or treated. Furthermore, it shows that metabolic syndrome and obesity can be prevented and / or treated. Furthermore, for example, it is considered that a compound known to function as an agonist of GC-A like BNP, such as ANP, has the same effect as BNP. Similarly, not only shows that cGKI can be activated to prevent and / or treat fatty liver, but also fatty liver associated with metabolic syndrome such as obesity and diabetes (or represented by obesity and diabetes). (Hepatic steatosis with metabolic syndrome) can be prevented and / or treated. Furthermore, it shows that metabolic syndrome and obesity can be prevented.
したがって、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを投与することによる脂肪肝の予防および／または治療方法を提供する。
また、本発明は、ｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）の活性化剤を投与することによる脂肪肝の予防および／または治療方法を提供する。
また、本発明は、ナトリウム利尿ペプチドの遺伝子を含有する脂肪肝の予防剤および／または治療剤を提供する。
また、本発明は、ｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）の遺伝子を含有する脂肪肝の予防剤および／または治療剤を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する脂肪肝の予防剤および／または治療剤を提供する。
また、本発明は、ｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）の活性化剤を含有する脂肪肝の予防剤および／または治療剤を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有するメタボリックシンドローム患者の脂肪肝の予防剤および／または治療剤を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する脂肪肝の治療用キットを提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有するメタボリックシンドロームの予防剤および／または治療剤を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する肥満の予防剤および／または治療剤を提供する。
また、本発明は、ナトリウム利尿ペプチドの遺伝子の、脂肪肝の予防剤および／または治療剤製造のための使用を提供する。
また、本発明は、ｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）の遺伝子の、脂肪肝の予防剤および／または治療剤製造のための使用を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストの、脂肪肝の予防剤および／または治療剤製造のための使用を提供する。
また、本発明は、ｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）の活性化剤の、脂肪肝の予防剤および／または治療剤製造のための使用を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストの、メタボリックシンドローム患者の脂肪肝の予防剤および／または治療剤製造のための使用を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストの、メタボリックシンドロームの予防剤および／または治療剤製造のための使用を提供する。
また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストの、肥満の予防剤および／または治療剤製造のための使用を提供する。Therefore, the present invention provides a method for preventing and / or treating fatty liver by administering an agonist of natriuretic peptide receptor GC-A.
The present invention also provides a method for preventing and / or treating fatty liver by administering an activator of cGMP-dependent protein kinase I (cGKI).
The present invention also provides a prophylactic and / or therapeutic agent for fatty liver containing a gene for natriuretic peptide.
The present invention also provides a preventive and / or therapeutic agent for fatty liver containing the gene for cGMP-dependent protein kinase I (cGKI).
The present invention also provides a prophylactic and / or therapeutic agent for fatty liver containing an agonist of natriuretic peptide receptor GC-A.
The present invention also provides a preventive and / or therapeutic agent for fatty liver containing an activator of cGMP-dependent protein kinase I (cGKI).
The present invention also provides a prophylactic and / or therapeutic agent for fatty liver in patients with metabolic syndrome containing an agonist of natriuretic peptide receptor GC-A.
The present invention also provides a kit for treating fatty liver containing an agonist of natriuretic peptide receptor GC-A.
The present invention also provides a preventive and / or therapeutic agent for metabolic syndrome, which contains an agonist of natriuretic peptide receptor GC-A.
The present invention also provides a prophylactic and / or therapeutic agent for obesity containing an agonist of natriuretic peptide receptor GC-A.
The present invention also provides use of a natriuretic peptide gene for the production of a prophylactic and / or therapeutic agent for fatty liver.
The present invention also provides the use of a gene for cGMP-dependent protein kinase I (cGKI) for the production of a prophylactic and / or therapeutic agent for fatty liver.
The present invention also provides the use of an agonist of natriuretic peptide receptor GC-A for the production of a prophylactic and / or therapeutic agent for fatty liver.
The present invention also provides use of an activator of cGMP-dependent protein kinase I (cGKI) for producing a prophylactic and / or therapeutic agent for fatty liver.
The present invention also provides the use of an agonist of natriuretic peptide receptor GC-A for the production of a prophylactic and / or therapeutic agent for fatty liver in patients with metabolic syndrome.
The present invention also provides the use of an agonist of natriuretic peptide receptor GC-A for the production of a preventive and / or therapeutic agent for metabolic syndrome.
The present invention also provides the use of an agonist of natriuretic peptide receptor GC-A for the production of a prophylactic and / or therapeutic agent for obesity.
本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する医薬を用いて脂肪肝の予防および／または治療を可能とする。また、本発明は、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する医薬を用いて、メタボリックシンドロームに伴う脂肪肝（または、メタボリックシンドロームを伴う脂肪肝）の予防および／または治療を可能とする。さらに、メタボリックシンドロームや肥満の予防および／または治療を可能とする。 The present invention enables prevention and / or treatment of fatty liver using a medicament containing an agonist of natriuretic peptide receptor GC-A. In addition, the present invention enables prevention and / or treatment of fatty liver associated with metabolic syndrome (or fatty liver associated with metabolic syndrome) using a medicament containing an agonist of natriuretic peptide receptor GC-A. . Furthermore, it enables prevention and / or treatment of metabolic syndrome and obesity.
本発明は、脂肪肝の予防および／または治療を目的とするものであるが、その対象患者は、他の基礎疾患のない脂肪肝の患者であってもよく、また、例えばメタボリックシンドロームに伴う脂肪肝（または、メタボリックシンドロームを伴う脂肪肝）の患者であってもよい。また、本発明は、メタボリックシンドロームの患者や肥満の患者を治療対象としてもよい。 Although the present invention is intended for the prevention and / or treatment of fatty liver, the target patient may be a patient with fatty liver without other underlying diseases, and for example, fat associated with metabolic syndrome It may be a patient with liver (or fatty liver with metabolic syndrome). Further, the present invention may treat patients with metabolic syndrome and obese patients as treatment targets.
本発明で使用するナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストについては、ＧＣ−Ａに結合し、そのグアニレートシクラーゼを活性化する作用を有する化合物であれば、特に限定はなく用いることができるが、代表的なものとしてナトリウム利尿ペプチドが挙げられる。ナトリウム利尿ペプチドとしては、ＡＮＰやＢＮＰが代表的なものであるが、これらのナトリウム利尿ペプチドに限定されるものではなく、それらのアミノ酸配列の１ないし複数のアミノ酸が他のアミノ酸に置換されたものでもよく、また、それらのアミノ酸配列の１ないし複数のアミノ酸が欠失したものでもよく、また、アミノ酸配列の１ないし複数のアミノ酸が欠失するとともにアミノ酸配列の１ないし複数のアミノ酸が他のアミノ酸に置換されたものでもよく、さらには、化学合成的に１ないし複数のアミノ酸が人工的なアミノ酸類似のものに置換されたものでもよい。また、化学合成や天然物由来の低分子の化合物であってもよい。 The agonist of natriuretic peptide receptor GC-A used in the present invention is not particularly limited as long as it is a compound that binds to GC-A and has an action of activating guanylate cyclase. However, a typical example is a natriuretic peptide. Typical examples of natriuretic peptides are ANP and BNP, but are not limited to these natriuretic peptides, and those in which one or more amino acids in the amino acid sequence are substituted with other amino acids. In addition, one or more amino acids of those amino acid sequences may be deleted, one or more amino acids of the amino acid sequence may be deleted, and one or more amino acids of the amino acid sequence may be other amino acids. In addition, one or a plurality of amino acids may be chemically synthetically substituted with an artificial amino acid-like one. Further, it may be a low molecular weight compound derived from chemical synthesis or a natural product.
ＡＮＰとしては、例えばＢｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，１１８巻，１３１頁，１９８４年に記載のヒト由来α−ｈＡＮＰを用いることができ、このＡＮＰは、一般名カルペリチド（ｃａｒｐｅｒｉｔｉｄｅ）として販売（商品名：ハンプ、ＨＡＮＰ）されている。α−ｈＡＮＰは、一般的にはＨｕｍａｎ ｐｒｏ−ＡＮＰ［９９−１２６］としても知られている。また、ＢＮＰとしては、例えばＢｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，１５９巻，１４２０頁，１９８９年に記載のヒトＢＮＰを用いることができ、このＢＮＰは一般名ネシリチド（ｎｅｓｉｒｉｔｉｄｅ）として販売（商品名：ナトレコール、Ｎａｔｒｅｃｏｒ）されている。 As ANP, for example, Biochem. Biophys. Res. Commun. 118, 131, 1984, human-derived α-hANP can be used, and this ANP is sold under the general name carperitide (trade name: HAMP, HANP). α-hANP is also commonly known as Human pro-ANP [99-126]. As BNP, for example, Biochem. Biophys. Res. Commun. 159, 1420, 1989, and this BNP is sold under the generic name nesiritide (trade name: Natrecor).
ナトリウム利尿ペプチドの１ないし複数のアミノ酸が他のアミノ酸に置換された例としては、例えば、ヒトＡＮＰの１２位のＭｅｔがＩｌｅに置換されたラットα−ｒＡＮＰ（Ｂｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，１２１巻，５８５頁，１９８４年）が挙げられる。また、１ないし複数のアミノ酸が欠失した例としては、例えば、Ｎ末のＳｅｒ−Ｌｅｕ−Ａｒｇ−Ａｒｇ−Ｓｅｒ−Ｓｅｒが欠失したＡＮＰが挙げられる。この様なＡＮＰまたはＢＮＰ誘導体に関しては、例えば、Ｍｅｄｉｃｉｎａｌ Ｒｅｓｅａｒｃｈ Ｒｅｖｉｅｗ，１０巻，１１５頁，１９９０年に記載されている一連の誘導体が挙げられ、それらは引用されている文献に記載の方法により入手または製造可能である。
また、アミノ酸配列の１ないし複数のアミノ酸が欠失するとともにアミノ酸配列の１ないし複数のアミノ酸が他のアミノ酸に置換された例としては、例えば、１５アミノ酸残基から成るｍｉｎｉ−ＡＮＰ（Ｓｃｉｅｎｃｅ，２７０巻，１６５７頁，１９９５年）が挙げられる。Examples of the substitution of one or more amino acids of the natriuretic peptide with other amino acids include, for example, rat α-rANP (Biochem. Biophys. Res. Commun., Met at
In addition, as an example in which one or more amino acids in the amino acid sequence are deleted and one or more amino acids in the amino acid sequence are substituted with other amino acids, for example, mini-ANP (Science, 270) consisting of 15 amino acid residues. Volume, 1657, 1995).
上記のＡＮＰ、ＢＮＰ、およびそれらの誘導体は、遺伝子工学的・細胞工学的な手法を用いて生産したものであってもよく、化学合成したものであってもよく、さらにはそれらを酵素処理や化学処理してアミノ酸残基を修飾またはアミノ酸配列の一部を除去したものであってもよい。 The above ANP, BNP, and derivatives thereof may be produced using genetic engineering / cell engineering techniques, may be chemically synthesized, and may be further treated with an enzyme treatment or the like. The amino acid residue may be modified by chemical treatment or a part of the amino acid sequence may be removed.
ナトリウム利尿ペプチド受容体ＧＣ−ＡのアゴニストとしてのＡＮＰやＢＮＰ等のナトリウム利尿ペプチドは、薬学的に許容される塩としてもよく、例えば塩酸、硫酸、リン酸等の無機酸との塩としてもよく、あるいはギ酸、酢酸、酪酸、コハク酸、クエン酸等の有機酸との塩としてもよい。また、ナトリウム、カリウム、リチウム、カルシウム等の金属塩としてもよく、トリエチルアミン等の有機塩基との塩としてもよい。また、ＡＮＰやＢＮＰ等のナトリウム利尿ペプチドまたはそれらの塩は、薬学的に許容される賦形剤、等張化剤、ｐＨ調節剤、希釈剤などと混合して静脈内投与、筋肉内投与、皮下投与、経鼻投与、経肺投与、舌下投与等の非経口的な投与方法で投与することが好ましい。また、これらのナトリウム利尿ペプチドまたはその塩は、リポソームやマイクロカプセルに封入して非経口的に投与してもよく、徐放製剤として患者の体内に埋め込んでもよい。 The natriuretic peptide such as ANP or BNP as an agonist of the natriuretic peptide receptor GC-A may be a pharmaceutically acceptable salt, for example, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid. Or a salt with an organic acid such as formic acid, acetic acid, butyric acid, succinic acid or citric acid. Moreover, it is good also as metal salts, such as sodium, potassium, lithium, and calcium, and is good also as salts with organic bases, such as a triethylamine. In addition, natriuretic peptides such as ANP and BNP or their salts are mixed with pharmaceutically acceptable excipients, isotonic agents, pH adjusters, diluents, etc., administered intravenously, intramuscularly, It is preferable to administer by parenteral administration methods such as subcutaneous administration, nasal administration, pulmonary administration, and sublingual administration. In addition, these natriuretic peptides or salts thereof may be administered parenterally by encapsulating them in liposomes or microcapsules, or may be implanted in a patient's body as a sustained release preparation.
ＡＮＰやＢＮＰ等のナトリウム利尿ペプチドまたはそれらの塩を投与する場合には、例えば凍結乾燥製剤を注射用水に溶解して微量輸液ポンプ（それがない場合には、小児用微量輸液セット）を用いて連続投与すればよい。ナトリウム利尿ペプチドは、前述のように血管を弛緩・拡張し血圧を低下させる作用を有することから、脂肪肝の予防および／または治療に当たっては、血圧を必要以上に低下させない速度で投与することが好ましく、投与時および投与直後には血圧をモニターすることが推奨される。ＡＮＰやＢＮＰ等のナトリウム利尿ペプチドまたはそれらの塩の１日の投与量は、０．１μｇ／ｋｇ〜１００ｍｇ／ｋｇの範囲であるが、０．５μｇ／ｋｇ〜５ｍｇ／ｋｇが好ましい。投与方法について詳細に述べるならば、ＡＮＰを投与する場合には、例えば、ＡＮＰの１０００μｇを注射用水１０ｍＬに溶解し、“体重×０．０６ｍＬ／時間”の速度（０．１μｇ／ｋｇ／分の投与速度）で投与することが考えられる。投与速度は、上記の速度に限られることなく、その１／２または１／４の速度でもよい。ＢＮＰを投与する場合には、２μｇ／ｋｇをボーラス投与した後、０．０１μｇ／ｋｇを連続投与することが考えられる。この場合にも、血圧を必要以上に低下させない速度で投与することが好ましく、投与時および投与直後には血圧をモニターすることが推奨される。ＡＮＰやＢＮＰが上記の投与速度で血圧や心拍数等に大きな影響を与えない場合には、さらに投与速度を上げてもよい。なお、その他のＡＮＰ誘導体またはＢＮＰ誘導体に関しては、その活性と持続性を考慮して、投与速度を決定すればよい。 When administering a natriuretic peptide such as ANP or BNP or a salt thereof, for example, a lyophilized preparation is dissolved in water for injection and a micro infusion pump (in the case of absence, a micro infusion set for children) is used. What is necessary is just to administer continuously. Since natriuretic peptide has the action of relaxing and dilating blood vessels and lowering blood pressure as described above, it is preferable to administer at a rate that does not lower blood pressure more than necessary for the prevention and / or treatment of fatty liver. It is recommended to monitor blood pressure during and immediately after administration. The daily dose of natriuretic peptides such as ANP and BNP or their salts is in the range of 0.1 μg / kg to 100 mg / kg, preferably 0.5 μg / kg to 5 mg / kg. When the administration method is described in detail, when ANP is administered, for example, 1000 μg of ANP is dissolved in 10 mL of water for injection, and the rate of “body weight × 0.06 mL / hour” (0.1 μg / kg / min) is obtained. It is conceivable to administer at an administration rate). The administration rate is not limited to the above-mentioned rate, and may be 1/2 or 1/4 of the rate. When administering BNP, it is conceivable to administer 0.01 μg / kg continuously after bolus administration of 2 μg / kg. Also in this case, it is preferable to administer the blood pressure at a rate that does not lower the blood pressure more than necessary, and it is recommended to monitor the blood pressure at the time of administration and immediately after administration. If ANP or BNP does not significantly affect blood pressure, heart rate, etc. at the above administration rate, the administration rate may be further increased. For other ANP derivatives or BNP derivatives, the administration rate may be determined in consideration of the activity and persistence.
また、上記のいずれの薬剤を使用する場合にも、投与期間は、脂肪肝の治療効果が得られるまでとすることが好ましく、継続的に投与してもよく、また間欠的に投与してもよい。脂肪肝の治療効果は、血液学的な検査で血中の中性脂肪、コレステロール値、ＧＯＴ、ＧＰＴを測定することでもよいが、超音波検査やＣＴ検査により判断することが好ましい。 In addition, when any of the above drugs is used, the administration period is preferably until a therapeutic effect for fatty liver is obtained, and may be administered continuously or intermittently. Good. The therapeutic effect of fatty liver may be determined by measuring blood neutral fat, cholesterol level, GOT, GPT by hematological examination, but is preferably judged by ultrasonic examination or CT examination.
また、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する脂肪肝の治療用キットとしては、ＡＮＰやＢＮＰ等のナトリウム利尿ペプチドまたはそれらの塩を凍結乾燥製剤として封入したバイアルとそれを溶解するための注射用水を組み合わせてキットとしたものが挙げられ、また溶解・投与に使用する注射用シリンジをそれらに組み合わせてもよく、さらには微量輸液ポンプや小児用微量輸液セットを組み合わせてもよい。 In addition, as a kit for treating fatty liver containing an agonist of natriuretic peptide receptor GC-A, a vial in which a natriuretic peptide such as ANP or BNP or a salt thereof is enclosed as a lyophilized preparation and its dissolution are used. Injectable water is used as a kit, and a syringe for use in dissolution and administration may be combined therewith, and a microinfusion pump or a pediatric microinfusion set may be combined.
ｃＧＫＩの活性化剤としては、ｃＧＭＰそのものを用いることもできるが、安定な８−ブロモｃＧＭＰ等の化学合成されたｃＧＭＰ誘導体を用いてもよく、さらには８−ブロモｃＧＭＰを分解するホスホジエステラーゼに対する安定性を増強させた誘導体（Ｐｈａｒｍａｃｏｌ．Ｔｈｅｒ．，８７巻，１９９頁，２０００年）を用いてもよい。また、このようなｃＧＭＰ誘導体とは異なる化学構造を有する低分子のｃＧＫＩの活性化剤を用いてもよい。 As an activator of cGKI, cGMP itself can be used, but a chemically synthesized cGMP derivative such as stable 8-bromocGMP may be used, and further, stability against phosphodiesterase that degrades 8-bromocGMP. (Pharmacol. Ther., 87, 199, 2000) may be used. Moreover, you may use the activator of the low molecular weight cGKI which has a chemical structure different from such a cGMP derivative.
ＡＮＰの遺伝子としては、Ｓｃｉｅｎｃｅ，２２６巻，１２０６頁，１９８４年に記載されているものを用いればよい。また、ＢＮＰの遺伝子としては、Ｂｉｏｃｈｅｍ．Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，１６５巻，６５０頁，１９８９年に記載されているものを用いればよい。ｃＧＭＰ依存性プロテインカイネースＩ（ｃＧＫＩ）の遺伝子としては、Ｈｙｐｅｒｔｅｎｓｉｏｎ，２７巻，５５２頁，１９９６年に記載されているｃＤＮＡを用いればよい。上記の遺伝子を用いて治療を行う場合には、レトロウイルス、アデノウイルス、アデノ随伴ウイルスあるいは人工ベクターをベクターとして用いて、筋肉注射や局所注射により遺伝子を導入すればよい。また、上記のようなベクターを使用せず、プラスミドの形で遺伝子を導入してもよい。具体的な遺伝子治療の方法については、実験医学，１２巻，３０３頁，１９９４年に記載の方法またはそれに引用されている文献の方法等を用いればよい。 As the gene for ANP, those described in Science, 226, 1206, 1984 may be used. In addition, as a gene of BNP, Biochem. Biophys. Res. Commun. 165, 650, 1989 may be used. As a gene for cGMP-dependent protein kinase I (cGKI), cDNA described in Hypertension, 27, 552, 1996 may be used. When treatment is performed using the above gene, the gene may be introduced by intramuscular injection or local injection using a retrovirus, adenovirus, adeno-associated virus or an artificial vector as a vector. Moreover, you may introduce | transduce a gene in the form of a plasmid, without using the above vectors. As a specific gene therapy method, a method described in Experimental Medicine, Vol. 12, page 303, 1994, or a method cited in the literature may be used.
本発明の脂肪肝の予防や治療は、その成因によらず脂肪肝全般について適用できるが、メタボリックシンドロームにより誘発される脂肪肝の予防や治療に好適に用いることができる。また、ナトリウム利尿ペプチド受容体ＧＣ−Ａのアゴニストを含有する上記の脂肪肝の予防や治療に関する記載は、メタボリックシンドロームや肥満の予防や治療においても同様である。 The prevention and treatment of fatty liver according to the present invention can be applied to all fatty livers regardless of their origin, but can be suitably used for the prevention and treatment of fatty liver induced by metabolic syndrome. In addition, the description regarding the prevention and treatment of fatty liver containing the natriuretic peptide receptor GC-A agonist is the same in the prevention and treatment of metabolic syndrome and obesity.
以下に試験例を示して本発明を説明する。 Hereinafter, the present invention will be described with reference to test examples.
［試験例１］
野生型マウスと肝臓特異的にＢＮＰを過剰発現させたマウス（以下、ＢＮＰ−Ｔｇマウス）に標準食と高脂肪食を与えて、脂肪肝の進展抑制作用を検討した。ＢＮＰ−Ｔｇマウスは、Ｊ．Ｃｌｉｎｉｃａｌ Ｉｎｖｅｓｔ．，９３巻、１９１１頁，１９９４年に記載の方法で作製した。
標準食と高脂肪食（熱量比で６０％：Ｒｅｓｅａｒｃｈ ｄｉｅｔ社、カタログ番号：Ｄ１２４９２）を各々１０週齢以降の野生型マウスおよびＢＮＰ−Ｔｇマウス（各１０匹）に１０週間与えた。体重は、６週齢から１週間ごとに測定した。標準食と高脂肪食の投与終了後、肝臓を摘出し、その重量を測定した。また、肝臓をホモジナイズした後、クロロフォルム・メタノール法で脂質を抽出し、中性脂肪測定キット（和光純薬工業、カタログ番号：４３２−４０２０１）を用いて肝臓内の中性脂肪含量を測定した。
さらに、皮下および腸間膜の脂肪組織を分離し、その重量を測定した。さらに採取した皮下脂肪組織から組織切片を作成し、これをＨＥ染色に付し、マウス一匹につき４視野（１００倍視野）観察し、脂肪細胞の平均面積を計測した。[Test Example 1]
A normal diet and a high-fat diet were given to wild-type mice and mice overexpressing BNP specifically in the liver (hereinafter referred to as BNP-Tg mice), and the effect of inhibiting the progression of fatty liver was examined. BNP-Tg mice are Clinical Invest. 93, page 1911, 1994.
A standard diet and a high fat diet (60% in terms of calorie ratio: Research diet, catalog number: D12492) were given to wild-type mice and BNP-Tg mice (10 mice each) after 10 weeks of age for 10 weeks. Body weight was measured every week from 6 weeks of age. After the administration of the standard diet and the high fat diet, the liver was removed and its weight was measured. Moreover, after homogenizing the liver, lipids were extracted by the chloroform-methanol method, and the neutral fat content in the liver was measured using a neutral fat measurement kit (Wako Pure Chemical Industries, catalog number: 432-40201).
In addition, the subcutaneous and mesenteric adipose tissue was separated and weighed. Further, a tissue section was prepared from the collected subcutaneous adipose tissue, this was subjected to HE staining, 4 fields (100 times field) were observed per mouse, and the average area of adipocytes was measured.
＜結果＞
標準食投与群では、野生型マウス（Ｗｔ）とＢＮＰ−Ｔｇマウスの体重に差はなかったが、高脂肪食投与群では、ＢＮＰ−Ｔｇマウスの体重は野生型マウスに比較して高脂肪食投与開始３週後より有意に低値を示した（図１）。
また、高脂肪食投与群では、ＢＮＰ−Ｔｇマウスの肝重量と肝臓内の中性脂肪含量が野生型マウスに比較して有意に低い値を示した（図２および図３）。
高脂肪食投与群では、ＢＮＰ−Ｔｇマウスの皮下脂肪組織量、腸間膜脂肪組織量はそれぞれ正常マウスと比して少なかった。さらに、皮下脂肪組織と腸間膜脂肪組織を合計した脂肪組織総重量は、標準食、高脂肪食、いずれを給餌した場合においても、ＢＮＰ−Ｔｇマウスの方が少なかった（図４Ａ−Ｃ）。さらに、高脂肪食投与群の腸間膜脂肪組織の脂肪細胞の平均面積は、ＢＮＰ―Ｔｇマウスの方が有意に少なかった。（図４Ｄ）<Result>
In the standard diet administration group, there was no difference in body weight between the wild type mouse (Wt) and the BNP-Tg mouse, but in the high fat diet administration group, the body weight of the BNP-Tg mouse was higher than that of the wild type mouse. The value was significantly lower than 3 weeks after the start of administration (FIG. 1).
In the high-fat diet administration group, the liver weight of the BNP-Tg mice and the neutral fat content in the liver were significantly lower than those of the wild-type mice (FIGS. 2 and 3).
In the high fat diet administration group, the amount of subcutaneous adipose tissue and the amount of mesenteric adipose tissue of BNP-Tg mice were lower than those of normal mice. Furthermore, the total weight of the adipose tissue obtained by adding the subcutaneous adipose tissue and the mesenteric adipose tissue was less in the BNP-Tg mice when either the standard diet or the high fat diet was fed (FIGS. 4A-C). . Furthermore, the average area of adipocytes in the mesenteric adipose tissue of the high fat diet administration group was significantly smaller in the BNP-Tg mice. (Fig. 4D)
［試験例２］
１０週齢以降の野生型マウス（１２匹）およびＢＮＰ−Ｔｇマウス（８匹）に熱量比で６０％の高脂肪食（Ｒｅｓｅａｒｃｈ ｄｉｅｔ社、カタログ番号：Ｄ１２４９２）をそれぞれ１０週間与えた。２４時間絶食後、ブドウ糖１．０ｇ／ｋｇを腹腔内に投与し、ブドウ糖投与前、投与後１５分、３０分、６０分、１２０分における血糖値を測定した。
また、上記と同様に高脂肪食を与えたマウスを６時間絶食後、インスリン０．７５Ｕ／ｋｇを腹腔内に投与し、インスリン投与前、投与後１５分、３０分、６０分、１２０分における血糖値を測定した。
血液は尾静脈より採取し、デキスターＺＩＩ（バイエル社）を用いて血糖値を測定した。[Test Example 2]
Wild type mice (12 mice) and BNP-Tg mice (8 mice) after 10 weeks of age were given a high fat diet (Research diet, catalog number: D12492) at a calorie ratio for 10 weeks. After fasting for 24 hours, glucose 1.0 g / kg was administered intraperitoneally, and blood glucose levels were measured before administration of glucose and at 15, 30, 60 and 120 minutes after administration.
In addition, as described above, mice fed with a high fat diet were fasted for 6 hours, and then insulin 0.75 U / kg was administered intraperitoneally, before insulin administration, at 15 minutes, 30 minutes, 60 minutes, and 120 minutes after administration. The blood glucose level was measured.
Blood was collected from the tail vein and blood glucose level was measured using Dexter ZII (Bayer).
＜結果＞
ＢＮＰ−Ｔｇマウスの血糖値は、野生型マウスに比較して、ブドウ糖投与後およびインスリン投与後に有意に低い値を示した（図５および図６）。この結果は、ＢＮＰ−Ｔｇマウスにおいて耐糖能およびインスリン感受性が改善されていることを示唆する。<Result>
The blood glucose level of BNP-Tg mice was significantly lower after glucose administration and after insulin administration compared to wild type mice (FIGS. 5 and 6). This result suggests improved glucose tolerance and insulin sensitivity in BNP-Tg mice.
［試験例３］
野生型マウスと全身性にｃＧＭＰ依存性プロテインカイネースＩを過剰発現させたマウス（以下、ｃＧＫ−Ｔｇマウス）に標準食と高脂肪食を与えて、脂肪肝の進展抑制作用を検討した。ｃＧＫ−Ｔｇマウスは、Ｐｒｏｃ．Ｎａｔｌ．Ａｃａｄ．Ｓｃｉ．ＵＳＡ，１００巻、３４０４頁，２００３年に記載の方法で作製した。
標準食と高脂肪食（熱量比で６０％：Ｒｅｓｅａｒｃｈ ｄｉｅｔ社、カタログ番号：Ｄ１２４９２）を１０週齢以降の野生型マウスおよびｃＧＫ−Ｔｇマウス（各１２匹）にそれぞれ１０週間与えた。体重は、６週齢から１週間ごとに測定した。高脂肪食投与終了後、肝臓を摘出し、その重量を測定した。また、肝臓をホモジナイズした後、クロロフォルム・メタノール法で脂質を抽出し、中性脂肪測定キット（和光純薬工業、カタログ番号：４３２−４０２０１）を用いて肝臓内の中性脂肪含量を測定した。さらに、試験例１と同様の方法で、各脂肪組織の重量と脂肪細胞の平均面積を計測した。[Test Example 3]
A standard diet and a high-fat diet were given to wild-type mice and mice in which cGMP-dependent protein kinase I was overexpressed systemically (hereinafter, cGK-Tg mice), and the effect of inhibiting the development of fatty liver was examined. cGK-Tg mice were obtained from Proc. Natl. Acad. Sci. USA, 100, 3404, 2003.
A standard diet and a high fat diet (60% in terms of calorie ratio: Research diet, catalog number: D12492) were given to 10-week-old wild-type mice and cGK-Tg mice (12 mice each) for 10 weeks. Body weight was measured every week from 6 weeks of age. After the administration of the high fat diet, the liver was removed and its weight was measured. Moreover, after homogenizing the liver, lipids were extracted by the chloroform-methanol method, and the neutral fat content in the liver was measured using a neutral fat measurement kit (Wako Pure Chemical Industries, catalog number: 432-40201). Further, the weight of each adipose tissue and the average area of adipocytes were measured by the same method as in Test Example 1.
＜結果＞
標準食投与群および高脂肪食投与群において、ｃＧＫ−Ｔｇマウスの体重は、野生型マウスに比較して有意に低い値を示した（図７）。
また、高脂肪食を投与したｃＧＫ−Ｔｇマウスにおいては、野生型マウスに比較して肝重量と肝臓内の中性脂肪含量が有意に低い値を示した（図８および図９）。皮下脂肪組織重量、腸間膜脂肪組織重量さらにそれらの合計である、総脂肪組織重量いずれについても、食事の内容によらず、ｃＧＫ−Ｔｇマウスの方が低い値を示した（図１０Ａ−Ｄ）。<Result>
In the standard diet administration group and the high fat diet administration group, the body weight of the cGK-Tg mice was significantly lower than that of the wild type mice (FIG. 7).
Further, in the cGK-Tg mice administered with the high fat diet, the liver weight and the neutral fat content in the liver were significantly lower than those in the wild type mice (FIGS. 8 and 9). The cGK-Tg mice showed lower values for the subcutaneous fat tissue weight, the mesenteric adipose tissue weight, and the total adipose tissue weight, which is the sum of them, regardless of the content of the meal (FIGS. 10A-D). ).
［試験例４］
１０週齢以降の野生型マウスおよびｃＧＫ−Ｔｇマウス（各８匹）に熱量比で６０％の高脂肪食（Ｒｅｓｅａｒｃｈ ｄｉｅｔ社、カタログ番号：Ｄ１２４９２）をそれぞれ１０週間与えた。２４時間絶食後、ブドウ糖１．０ｇ／ｋｇを腹腔内に投与し、ブドウ糖投与前、投与後１５分、３０分、６０分、１２０分における血糖値を測定した。
また、上記と同様に高脂肪食を与えたマウスを６時間絶食後、インスリン０．７５Ｕ／ｋｇを腹腔内に投与し、インスリン投与前、投与後１５分、３０分、６０分、１２０分における血糖値を測定した。
血液は尾静脈より採取し、デキスターＺＩＩ（バイエル社）を用いて血糖値を測定した。[Test Example 4]
A 60% high fat diet (Research diet, catalog number: D12492) was given to a wild-type mouse and a cGK-Tg mouse (each 8 mice) after 10 weeks of age for 10 weeks, respectively. After fasting for 24 hours, glucose 1.0 g / kg was administered intraperitoneally, and blood glucose levels were measured before administration of glucose and at 15, 30, 60 and 120 minutes after administration.
In addition, as described above, mice fed with a high fat diet were fasted for 6 hours, and then insulin 0.75 U / kg was administered intraperitoneally, before insulin administration, at 15 minutes, 30 minutes, 60 minutes, and 120 minutes after administration. The blood glucose level was measured.
Blood was collected from the tail vein and blood glucose level was measured using Dexter ZII (Bayer).
＜結果＞
ｃＧＫ−Ｔｇマウスの血糖値は、野生型マウスに比較して、ブドウ糖投与後およびインスリン投与後に有意に低い値を示した（図１１および図１２）。この結果は、ｃＧＫ−Ｔｇマウスにおいて耐糖能およびインスリン感受性が改善されていることを示唆する。<Result>
The blood glucose level of cGK-Tg mice was significantly lower after glucose administration and after insulin administration compared to wild type mice (FIGS. 11 and 12). This result suggests improved glucose tolerance and insulin sensitivity in cGK-Tg mice.
［試験例５］
野生型マウスおよびｃＧＫ−Ｔｇを１０週齢まで通常食（Ｆ−２，船橋農場）で飼育。１０週齢から２０週齢まで高脂肪食（６０ｋｃａｌ％ ｆａｔ，Ｄ１２４９２，Ｒｅｓｅａｒｃｈ Ｄｉｅｔ）で飼育した後、明期に自由摂食下で、ペントバルビタール麻酔下に解剖し、肩甲骨間褐色脂肪組織、大腿四頭筋組織、肝臓を摘出。直ちに液体窒素で凍結し、−８０℃で保存した。凍結保存組織からＲＮｅａｓｙ ｍｉｎｉ ｋｉｔ ｆｏｒ ｌｉｐｉｄ ｔｉｓｓｕｅ（Ｑｉａｇｅｎ）にてｔｏｔａｌ ＲＮＡを抽出し、ＥｘＳｃｒｉｐｔ ＲＴ ｒｅａｇｅｎｔ ｋｉｔ（Ｔａｋａｒａ ＢＩＯ）にてｃＤＮＡ化した。各遺伝子に特異的なプライマーセット（Ｔａｋａｒａ ＢＩＯ）とＳｙｂｅｒ Ｐｒｅｍｉｘ ＥｘＴａｑ（Ｔａｋａｒａ ＢＩＯ）を用いて、ＡＢＩ７３００ Ｒｅａｌ−Ｔｉｍｅ ＰＣＲ Ｓｙｓｔｅｍ（Ａｐｐｌｉｅｄ Ｂｉｏｓｙｓｔｅｍｓ）にて遺伝子発現を検討した。
ｃＧＫ−Ｔｇの肩甲骨間褐色脂肪組織では、熱産生を亢進させてエネルギー消費を高めるｐｅｒｏｘｉｓｏｍｅ ｐｒｏｌｉｆｅｒａｔｏｒｓ−ａｃｔｉｖａｔｅｄ ｒｅｃｅｐｔｏｒ γ ｃｏ−ａｃｔｉｖａｔｏｒ（ＰＧＣ）−１αとｕｎｃｏｕｐｌｉｎｇ ｐｒｏｔｅｉｎ（ＵＣＰ）−１の遺伝子発現が、野生型マウスの約３倍に亢進していた（図１３）。ｃＧＫ−Ｔｇの骨格筋では、野生型と比較して、熱産生を亢進させてエネルギー消費を高める遺伝子群（ＰＧＣ−１α、ＵＣＰ−３）の発現亢進に加えて、脂肪酸酸化を活性化させるＰＰＡＲαとＰＰＡＲδの遺伝子発現にも亢進が認められた（図１４）。ｃＧＫ−Ｔｇの肝臓においても、野生型と比較して、ＰＰＡＲδ遺伝子発現の亢進が認められた（図１５）。以上より、ＧＣ−Ａ系のエフェクター分子であるｃＧＫの過剰発現による抗脂肪肝作用のメカニズムの少なくとも一部は、脂肪酸酸化の亢進を中心とした褐色脂肪組織、骨格筋、肝臓でのエネルギー消費の亢進によることが示唆された。[Test Example 5]
Wild-type mice and cGK-Tg were raised on a normal diet (F-2, Funabashi Farm) until 10 weeks of age. After being raised on a high fat diet (60 kcal% fat, D12492, Research Diet) from 10 to 20 weeks of age, dissected under pentobarbital anesthesia under free feeding in the light period, interscapular brown adipose tissue, The quadriceps tissue and liver were removed. Immediately frozen in liquid nitrogen and stored at -80 ° C. Total RNA was extracted from the cryopreserved tissue with RNeasy mini kit for lipid tissue (Qiagen), and was converted to cDNA with ExScript RT reagent kit (Takara BIO). Gene expression was examined in ABI7300 Real-Time PCR System (Applied Biosystems) using a primer set specific for each gene (Takara BIO) and Syber Premix ExTaq (Takara BIO).
In the interscapular brown adipose tissue of cGK-Tg, peroxisome proliferators-activated receptor γ co-activator (PGC) -1α and uncoupling protein (UCP) -1 gene expression is enhanced by increasing heat production and increasing energy consumption. It was about 3 times as high as that of type mice (FIG. 13). In the skeletal muscle of cGK-Tg, PPARα that activates fatty acid oxidation in addition to increased expression of genes (PGC-1α, UCP-3) that increase heat consumption and increase energy consumption compared to wild type And PPARδ gene expression was also enhanced (FIG. 14). Also in the liver of cGK-Tg, an increase in PPARδ gene expression was observed compared to the wild type (FIG. 15). From the above, at least part of the mechanism of anti-fatty liver action by overexpression of cGK, which is an effector molecule of the GC-A system, is due to energy consumption in brown adipose tissue, skeletal muscle, and liver centered on enhancement of fatty acid oxidation. It was suggested that it was due to enhancement.
［試験例６］
野生型マウスおよびＧＣ−Ａヘテロノックアウトマウス（ＧＣ−Ａ＋／−）を８週齢まで通常食（Ｆ−２，船橋農場）で飼育。８週齢から２０週齢まで高脂肪食（４５ｋｃａｌ％ ｆａｔ，Ｄ１２４５１，Ｒｅｓｅａｒｃｈ Ｄｉｅｔ）で飼育し、２０週齢にて明期に自由摂食下にて解剖した。
１４週齢以降でＧＣ−Ａ＋／−マウスで野生型よりも有意に体重増加が亢進していた（図１６）。２０週齢ではＧＣ−Ａ＋／−マウスで、野生型マウスと比較して、体重は有意に大きく、肝臓重量体重比と肝臓中性脂肪含量には大きい傾向が認められた（図１７）。総脂肪重量はＧＣ−Ａ＋／−マウスで、野生型よりも有意に増加していた（図１８）。摂餌量には野生型マウスとＧＣ−Ａ＋／−マウスの間に差は認められなかった（図１９）。また、高脂肪食による耐糖能の悪化は、ＧＣ−Ａ＋／−マウスで野生型よりも増強していた（図２０）。以上より、ＧＣ−Ａ＋／−マウスでは高脂肪食による肥満、脂肪肝形成が野生型マウスよりも大きく、耐糖能障害の程度も大きいことが示された。[Test Example 6]
Wild-type mice and GC-A hetero knockout mice (GC-A +/- ) were bred on a normal diet (F-2, Funabashi Farm) until 8 weeks of age. The animals were reared on a high fat diet (45 kcal% fat, D12451, Research Diet) from 8 to 20 weeks of age, and dissected under free feeding in the light period at 20 weeks of age.
After 14 weeks of age, weight gain was significantly increased in GC-A +/− mice compared to wild type (FIG. 16). At 20 weeks of age, GC-A +/− mice were significantly larger in body weight than the wild-type mice, and the liver weight-weight ratio and liver triglyceride content tended to be large (FIG. 17). Total fat weight was significantly increased in GC-A +/− mice compared to wild type (FIG. 18). There was no difference in food intake between wild-type mice and GC-A +/− mice (FIG. 19). Moreover, the deterioration of glucose tolerance due to a high-fat diet was enhanced in GC-A +/− mice compared to the wild type (FIG. 20). From the above, it was shown that in GC-A +/− mice, obesity and fatty liver formation due to a high-fat diet were larger than in wild-type mice, and the degree of impaired glucose tolerance was large.
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