We report here for the first time that high-fat feeding augments plasma LPS at a concentration sufficient to increase body weight, fasted glycemia, and inflammation.

LPS infusion in normal diet-fed mice causes a metabolic response similar, to some extent, to high-fat feeding.
普通の食事を与えているマウスへLPSを注入すると、高脂肪食を与えたマウスと (ある程度までは) 類似した代謝性の応答を引き起こす。

LPS receptor-deleted mice (i.e., CD14 mutants) are hypersensitive to insulin, and the occurrence of insulin resistance, obesity, and diabetes is delayed in response to high-fat feeding.
LPSの受容体を削除したマウス (すなわちCD14変異マウス) はインスリンへの感受性が高く、高脂肪食を与えても、インスリン抵抗性、肥満、糖尿病の発症が遅延する。

Hence, we conclude that the LPS/CD14 system sets the threshold at which high-fat diet-induced metabolic disease occurs.

※threshold: 閾値、限界値。興奮や反応を起こさせるのに必要な最小の値

Central to metabolic diseases is insulin resistance associated with a low-grade inflammatory status.

In our quest to determine a triggering factor of the early development of metabolic disease, we looked for a molecule involved early in the cascade of inflammation and identified LPS as a good candidate.

Furthermore, LPS is a strong stimulatory of the release of several cytokines that are key inducers of insulin resistance.

The concept of dietary excess is essentially linked to high-fat feeding-induced inflammation (24).
食事性過剰 (食事による栄養過剰とそれに伴う疾患) という概念は、本質的に、高脂肪食による炎症と関連している。

※the concept of dietary excess: 24では、「食欲不振 (anorexia)や神経的過食症 (bulimia nervosa)のような摂食障害 (eating disorders)では、炎症性サイトカイン (IL-1, IL-6, TNF-α)の異常が見られ、再栄養 (renutrition: 栄養の見直し / 栄養の補充)により正常値に回復した」とある

As we identified here, LPS as a putative factor for the triggering of metabolic diseases.

We needed to challenge our hypothesis within a pathological context.

※pathologic: 病理学。病気の本質、原因、および病的過程での構造や機能の変化を扱う

We fed mice a high-fat diet for a short period of 2-4 weeks and showed that high-fat diet increases the circulating concentration of plasma LPS.

Hence, we defined this increase in plasma LPS concentration induced by high-fat feeding as metabolic endotoxemia.

It is noteworthy that the endotoxemia reached was 10-50 times lower than that obtained during septic shock (22,25).

The mechanisms allowing enteric LPS absorption are unclear but could be related to an increased filtration of plasma LPS into lymph with fat absorption (26).

Endogenous LPS is continually produced within the gut by the death of Gram-negative bacteria (27) and is absorbed into intestinal capillaries (28,29) to be transported by lipoproteins (14,15).

Therefore, we assessed whether a high-fat diet changed intestinal microbiota and showed that among the dominant members of the intestine the Gram-negative Bacteroides-related bacteria MIB were significantly reduced in the high-fat diet-fed animals compared with control animals.
そして、コントロール食のマウスと比べて高脂肪食を与えたマウスでは、腸のグラム陰性菌であるバクテロイデス関連細菌の主要な構成種の中でもMIB (マウス腸細菌) が著しく減少していたことを示した。

However, numbers of the dominant Gram-positive group, the Eu. rectale-Cl. coccoides group, were also reduced, as were numbers of bifidobacteria, a group of bacteria that have been shown to reduce intestinal endotoxin (LPS) levels in mice and improve mucosal barrier function (30,31).
ビフィドバクテリウム属の細菌グループはマウスの腸のエンドトキシン (LPS) 濃度を減少させ、粘膜のバリア機能を改善することが示されている。

※LPS (LipoPolySaccharide): リポ多糖。グラム陰性菌の細胞壁外膜を構成するリポ(脂質)多糖。グラム陰性細菌が死ぬと内部から放出されるため、内 (endo) 毒素 (toxin) という

Supporting our conclusion, apart from further evidence from the literature, was the result that an acute ingestion of LPS, diluted in oil, reproduced high-fat diet-increased plasma LPS concentration.
オイルで希釈したLPSを急激に (胃管栄養で) 摂取させると、高脂肪食による血漿LPS濃度の上昇が再現されるという結果である。

Furthermore, oil by itself can acutely increase endotoxemia.

We could therefore suggest that plasma LPS levels depends on feeding status and are physiologically regulated nutrients.

We challenged this hypothesis in mice assessing endotoxemia throughout the day and showed that plasma LPS concentration increases progressively over the feeding period (night in the mouse).
その結果、通常の食事の間 (マウスでは夜中)は血漿LPS濃度が徐々に増加することを示した。

As the daily endotoxemia cycle was totally disrupted during high-fat feeding, our data showed that the fat content in food is an important regulator of plasma LPS concentration.

In light of the changes observed in the microbiota of high-fat diet-fed mice, one could suggest that an increased continuous intestinal absorption of LPS could maintain steady and elevated the endotoxemia.

Such a conclusion is also supported by our epidemiological study in humans in which healthy patients feeding on a fat-enriched diet were characterized by a higher fasting endotoxemia (data not shown).
その研究では、脂肪の豊富な食事を常食にしている健康な被験者は、空腹時の血中エンドトキシン量がより高いという特徴があった (データ未公開)。

To assess whether a two- to three-times-increased daily endotoxemia could be considered as a physiological regulator, glucose metabolism was assessed in mice in which we continuously infused a very low rate of LPS.

We found that the body and adipose depot weights and fasted glycemia were increased to the same extent as during high-fat feeding.

Furthermore, the chronic LPS infusion induced liver insulin resistance and was associated with fasted hyperinsulinemia.

As whole-body insulin resistance was not induced by the LPS infusion, our data showed the liver as a first target of LPS-induced insulin resistance.

The role of LPS as a regulator of energy metabolism has been proposed previously (32,33).

In most of the studies that described the anorectic and metabolic effects of LPS, endotoxemia was very elevated or given as single shot and witnessed a state of acute phase infection.

Here, we showed that the chronic infusion of a very low rate of LPS increased body weight.この点で我々は、非常に低い割合でLPSを慢性的に注入すると体重が増加することを示した。

However, this increase was not due to an excessive energy intake.

We then studied the CD14 mutant mice, in which the expression of the protein is suppressed by a point mutation (34).

※point mutation: 点変異、点突然変異。DNAの塩基の一つだけが変化することで、アミノ酸が変化したり (ミスセンス突然変異)、翻訳が途中で停止する (ナンセンス突然変異)

CD14 is a key molecule in innate immunity (35).

It is a multifunctional receptor phosphatidylinositol phosphate-anchored glycocoprotein of 55 kDa constitutively expressed in considerable amounts on the surface (mCD14) of mature monocytes, macrophages, and neutrophils (36,37).
ホスファチジルイノシトールリン酸にアンカー (固定) した5万5千ダルトンの糖タンパク質であり、成熟した単球・マクロファージ・好中球の表面で、構成的に (常に) かなりの量で発現している (膜CD14)。

※Da (dalton): ダルトン。炭素原子の同位体である「炭素12」の質量を12で割った量で、分子や原子の質量の単位として使われる

※mCD14 (membraneCD14): 膜CD14

phosphatidylinositol phosphate: ホスファチジルイノシトールリン酸。ホスファチジルイノシトールのヒドロキシル基にリン酸基がエステル結合したもの

The binding of LPS to the complex of mCD14 and TLR4 at the surface of the innate immune cells (15) triggers the secretion of proinflammatory cytokines (16), consequently affecting insulin action.

Mice depleted of the CD14 gene lack the innate immune response to bacterial LPS, and CD14-deficient macrophages do not secrete proinflammatory cytokines when stimulated with LPS (38).

We have shown here that CD14 mutant mice fed a normal diet were hypersensitive to insulin.我々は今回の研究で、通常の食事を与えたCD14変異マウスがインスリンへの感受性が高いことを示してきた。

Therefore, CD14 could clearly be an early modulator of insulin sensitivity and, indeed, when challenged by a high-fat diet for 1 month the insulin-hypersensitive CD14 mutant mice did not become insulin resistant, glucose intolerant, or diabetic.

However, after long-term feeding (24 weeks), the CD14 mutant mice did become insulin resistant and gained weight.
しかし、長期間 (24週間) 与えた後では、CD14変異マウスはインスリン抵抗性になり、体重が増えてしまった。

Furthermore, hepatic steatosis, as reflected by the triglyceride content, was totally prevented in CD14 mutants during long-term high-fat feeding.
さらに、肝臓の脂肪症 (脂肪肝) はトリグリセリド量を反映したものだが、CD14変異マウスでは長期間の高脂肪食の間でも完全に阻止された。

Hepatic steatosis is an early event because only 4 weeks of high-fat feeding were sufficient to increase the triglyceride content of wild-type mice.

※event: イベント。病気などの出来事

This could be mimicked by a 4-week LPS infusion.

Again, hepatic steatosis was totally blunted in CD14 mutant fed a high-fat diet or infused with LPS.

We could conclude that the LPS-CD14 system sets a threshold at which metabolic diseases occur.

Moreover, and relevant to our findings, epidemiological data from the literature showed statistical relationships between CD14 (39,40) inflammation, obesity, and insulin resistance in humans.

39: Activation of peripheral blood CD14+ monocytes occurs in diabetes. (末梢血CD14+単球は、糖尿病で活性化している)

40: CD14 monocyte receptor, involved in the inflammaroty cascade, and insulin sensitivity. (単球の受容体CD14は、炎症性カスケードとインスリン抵抗性に関与している)

by travelair4000ext | 2013-03-21 10:01 | 翻訳  

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