Intestinal Lipid Processing, Bile Acid Metabolism, and Pancreatic Islet Function

在美国，糖尿病的流行已经达到了流行的程度，给患者带来了严重的痛苦，并给社会带来了生产力损失和医疗费用的负担。糖尿病的特征是胰腺中的β细胞质量减少，或β细胞无法分泌足够的胰岛素来完全补偿胰岛素抵抗。增加或保留功能性β细胞群是预防或治疗糖尿病的一个有吸引力的目标；然而，我们没有足够的干预目标。我们研究的长期目标是更好地了解肠道脂肪处理如何控制全身代谢，并探索抗击代谢性疾病的干预靶点。我们已报道，酰基辅酶A：单甘油酰基转移酶2(MGAT2)介导肠道脂肪吸收，调节全身能量平衡。虽然缺乏功能性MGAT2基因(Mogat2-/-)或在肠道中缺乏MGAT2的小鼠吸收了正常数量的膳食脂肪，但它们表现出脂肪吸收延迟，能量消耗增加，以及对肥胖和相关疾病的抵抗力。有趣的是，我们发现MGAT2的缺失通过保留功能性的β细胞团来保护小鼠免受化学和遗传诱导的糖尿病。与这种保护相关的是，Mogat2-/-小鼠增加了血浆胆汁酸，众所周知，作为调节新陈代谢的膜和核受体的配体，胆汁酸具有强大的代谢作用。此外，通过喂养小鼠熊去氧胆酸、用广谱抗生素治疗小鼠或无菌饲养小鼠，增加血浆胆汁酸足以保护功能贝塔细胞群免受β细胞毒素链脲佐菌素的影响。有趣的是，我们还发现大多数肠道微生物群所在的盲肠中胆盐水解酶(BSH)活性降低，而胰腺α细胞中的GLP1活性增加。为了了解MGAT2缺乏介导的保护的生理和分子机制，我们建议严格检验我们的总体假设，即肠道MGAT2的缺失(1)降低了微生物的BSH活性，这(2)通过顶端钠依赖的胆盐转运体(ASBT)增强重吸收，导致(3)胰腺a细胞GLP1分泌增加，从而诱导b细胞GLP1受体(GLP1R)信号转导，从而保护胰岛功能。在目标1中，我们将确定降低BSH活性是否有必要和/或是否足以增加血浆胆汁酸并保护小鼠再次受到β细胞侮辱。在目标2中，我们将确定MGAT2的丢失是否会增强胆汁酸的重吸收，以及这一过程是否需要ASBT。在目标3中，我们将确定GLP1是否产生于阿尔法细胞，以及是否需要β细胞上的GLP1受体来发挥MGAT2缺乏的作用。我们提出的工作代表了阐明将肠道脂肪处理和胆汁酸代谢与胰岛功能联系起来的新途径的必要步骤。我们的发现将描述一个控制全身新陈代谢的器官间沟通的新例子，为通过减少细菌胆盐水解酶、增加结合初级胆汁酸和调节胰岛内信号而靶向抑制MGAT2来对抗糖尿病奠定基础。

The prevalence of diabetes has reached epidemic proportions in the United States, gravely afflicting patients and burdening societies with productivity loss and health care costs. Diabetes is characterized by a reduction in beta cell mass in the pancreas, or a failure of beta cells to secrete enough insulin to fully compensate for insulin resistance. Augmenting or preserving functional beta cell mass is an attractive objective for preventing or treating diabetes; however, we have insufficient intervention targets. The long-term goal of our research is to better understand how intestinal lipid processing controls systemic metabolism and explore intervention targets to combat metabolic diseases. We have reported that acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) mediates intestinal fat absorption and regulates systemic energy balance. Although mice lacking a functional MGAT2 gene (Mogat2–/–) or lacking MGAT2 specifically in the intestine absorb normal amounts of dietary fat, they exhibit delayed fat absorption, increased energy expenditure, and resistance to obesity and related disorders. Intriguingly, we found that loss of MGAT2 protects mice against chemically- and genetically-induced diabetes by preserving functional beta cell mass. Associated with the protection, Mogat2–/– mice have increased plasma bile acids, known to have potent metabolic effects as ligands for membrane and nuclear receptors that regulate metabolism. Further, increasing plasma bile acids – by feeding mice ursodeoxycholic acid, treating mice with broad-spectrum antibiotics, or raising mice germ-free– is sufficient to protect functional beta cell mass against the beta-cell toxin, streptozotocin. Intriguingly, we also found reduced bile salt hydrolase (BSH) activity in cecum, where most gut microbiota reside, and increased GLP1 in pancreatic alpha-cells. To understand the physiological and molecular mechanisms underlying MGAT2 deficiency-mediated protection, we propose here to rigorously test our overarching hypothesis that that loss of intestinal MGAT2 (1) decreases microbial BSH activity, which (2) enhances reabsorption through the apical sodium-dependent bile salt transporter (ASBT), leading to (3) increased GLP1 secretion from pancreatic a-cells that induces GLP1 receptor (GLP1r)-signaling in b-cells, and thereby protects pancreatic islet function. In Aim 1, we will determine if a reduction in BSH activity is necessary and/or sufficient to increase plasma bile acids and protect mice again beta cell insults. In Aim 2, we will determine if loss of MGAT2 enhances re-absorption of bile acids and if the process requires ASBT. In Aim 3, we will determine if GLP1 produced in alpha cells and if GLP1 receptors on beta cells are required for the effects of MGAT2 deficiency. Our proposed work represents essential steps to elucidate novel pathways that link intestinal lipid processing and bile acid metabolism with pancreatic islet function. Our findings will describe a novel example of interorgan communication that controls systemic metabolism setting the stage for targeting MGAT2 inhibition to combat diabetes by decreasing bacterial bile salt hydrolase, increasing conjugated primary bile acids, and modulating intra-islet signaling.