Dietary fat, lipoproteins, and lipopolysaccharide: role in insulin resistance

描述（由申请人提供）：肥胖与胰岛素抵抗和脂肪组织、肌肉和肝脏的慢性炎症有关，但这种炎症的机制尚不清楚。内毒素（脂多糖，LPS）由肠道来源的脂蛋白（乳糜微粒）携带，是膳食脂肪和炎症之间的联系。在乳糜微粒组装过程中，脂多糖和脂多糖结合蛋白（LBP）附着在颗粒上。血浆乳糜微粒部分的脂多糖在脂肪餐后短暂增加。乳糜微粒甘油三酯通过脂肪和肌肉脂蛋白脂肪酶（LpL）从血浆中清除；剩余的脂蛋白随后被肝脏清除。胰岛素抵抗/糖尿病和血浆脂多糖之间有很强的联系。肠道细菌和胰岛素抵抗之间的进一步联系在无菌小鼠或微生物群移植小鼠的许多实验中得到证实，这些实验显示饮食引起的肥胖和胰岛素抵抗的变化。我们假设乳糜微粒上的脂多糖在乳糜微粒TG脂解过程中被传递到脂肪组织、肌肉和肝脏，释放的脂多糖在这些组织中引发低度炎症反应，导致组织炎症和胰岛素抵抗。乳糜微粒脂解的缓慢过程，伴随持续的残余脂蛋白血症，可能与高暴露于脂多糖和随后的组织炎症有关。已经有大量关于啮齿动物的文献表明，通过各种免疫调节或微生物群的操纵，可以改变肥胖、炎症和胰岛素抵抗。这些问题还没有在人类身上得到很好的检验。本研究旨在确定肠道微生物群的改变是否会影响人类脂蛋白相关的LPS和胰岛素抵抗。具体目标我们将确定利福昔明对肠道菌群的改变是否会减少循环LPS。我们将测量肥胖MetS受试者在禁食状态和富含脂质的膳食后的血浆LPS。然后，受试者将接受抗生素利福昔明治疗8周，以大幅减少肠道细菌，这些细菌可以通过现有技术检测到。具体目标2。我们将确定利福昔明治疗后肠道微生物群的改变是否会减少脂肪炎症并改善胰岛素抵抗。受试者将接受基线脂肪活检和正糖钳来测量外周和肝脏胰岛素敏感性。然后，他们将接受利福昔明治疗，并进行胰岛素敏感性测试和活检，以确定微生物群的破坏是否会减少组织炎症并改善胰岛素敏感性。

DESCRIPTION (provided by applicant): Obesity is associated with insulin resistance and chronic inflammation in adipose tissue, muscle and liver and the mechanisms underlying this inflammation is not well understood. Endotoxin (lipopolysaccharide, LPS) is carried on gut-derived lipoproteins (chylomicrons) and provides a link between dietary fat and inflammation. During chylomicrons assembly, LPS and LPS binding protein (LBP) are attached to the particle. Plasma LPS in the chylomicron fraction transiently increases following a fatty meal. Chylomicron triglyceride is cleared from plasma by adipose and muscle lipoprotein lipase (LpL); remnant lipoproteins are then cleared by the liver. Strong associations between insulin resistance/diabetes and plasma LPS have been found. Further links between gut bacteria and insulin resistance are illustrated by many experiments in germ-free mice or in mice with microbiota transplants, which show changes in diet-induced obesity and insulin resistance. We hypothesize that the LPS on chylomicrons is delivered to adipose tissue, muscle and liver during chylomicron TG lipolysis, and the released LPS initiates a low-grade inflammatory reaction in these tissues that contributes to tissue inflammation and insulin resistance. A slow process of chylomicron lipolysis, with persistent remnant lipoproteinemia, may be associated with high exposure to LPS and consequent tissue inflammation. There is already an extensive literature in rodents demonstrating alterations in obesity, inflammation and insulin resistance with various immune modulations or manipulations of microbiota. These questions have not been well tested in humans. This study is intended to determine whether alteration of gut microbiota can impact human lipoprotein associated LPS and insulin resistance. Specific Aim 1. We will determine whether an alteration in the gut microbiota achieved with rifaximin will decrease circulating LPS. We will measure plasma LPS both in the fasting state and after a lipid-rich meal in obese MetS subjects. The subjects will then be treated with the antibiotic rifaximin for 8 weeks to substantially reduce gut bacteria, which can be detected by current techniques. Specific Aim 2. We will determine whether a change in the gut microbiota from rifaximin treatment will decrease adipose inflammation and improve insulin resistance. Subjects will undergo a baseline fat biopsy and a euglycemic clamp to measure peripheral and hepatic insulin sensitivity. They will then be treated with rifaximin and the insulin sensitivity testing ad biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation and improves insulin sensitivity.