Bye, bye, bile: how altered bile acid composition changes small intestinal lipid sensing.
Bye, bye, bile: how altered bile acid composition changes small intestinal lipid sensing.
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DOI：
10.1136/gutjnl-2020-320873
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发表时间：
2020-09
期刊：
影响因子：
24.5
通讯作者：
Lam TKT
中科院分区：
文献类型：
--
作者：
Duca FA;Lam TKT
胃肠道（GI）越来越被认为是影响肥胖进展的能量体内平衡的主要因素。肠道代表了进入的营养物质和宿主之间相互作用的第一个位点，产生关键的负反馈信号，可能通过改变胃肠道功能（如胃排空）来调节食物摄入。在近端肠脂质感知的情况下，已经确定了几种机制来驱动饱腹感和饱足感。例如，膳食脂肪被水解并吸收到肠细胞中。在上消化道，这刺激油酰乙醇胺（OEA）的合成，然后可以作为信号分子，通过激活过氧化物酶体增殖物激活受体-α和肠-脑轴诱导饱腹感。1或者，通过与G蛋白偶联受体-40结合的游离脂肪酸激活肠内分泌细胞（EECs），导致肠肽分泌，如胆囊收缩素和胰高血糖素样肽-1（GLP-1），减缓胃排空并减少食物摄入。有趣的是，假设通过游离脂肪酸激活EEC发生在基底外侧，需要乳糜微粒形成，因此膳食脂肪水解，类似于OEA生产。2鉴于胆汁酸，特别是小鼠中的胆酸，可抑制饮食中的脂质，从而促进脂质在小肠中的有效水解和吸收，它们的功能将涉及激活上述途径以降低食物摄入的必要性。在GUT中，Higuchi等人观察到Cyp 8b 1-/-小鼠由于食物摄入抑制而表现出体重减轻和肥胖。正如预期的那样，通过12α-羟化酶Cyp 8b 1敲除降低胆酸和其他12α-羟基化胆汁酸会损害膳食脂肪吸收。然而，他们通过确定胃排空是由较低的肠道脂质-肠肽信号传导轴引起的，巧妙地破译了解释体重意外下降和食物摄入量减少的机制。3 Cyp 8b 1-/-小鼠由于食物摄入的抑制而表现出体重减轻和肥胖。从机制上讲，Cyp 8b 1-/-小鼠实际上具有降低的再喂食空肠OEA水平，因此导致饱腹感增加的肠道OEA信号传导增加不是减少食物摄入的驱动机制。这与Cyp 8b 1-/-小鼠表现出膳食量减少而非餐间间隔减少的事实一致，表明食物摄入的减少是通过增加饱腹感而不是饱腹感。相反，作者将餐量减少归因于胃排空减慢。首先，作者确定胃排空的减少是脂质依赖性的，因为喂食无脂肪饮食消除了Cyp 8b 1-/-小鼠的摄食量和胃排空减少。其次，作者确定胃排空减慢是通过GPR 119信号传导介导的，因为Cyp 8b 1-/-小鼠中GPR 119的急性药理学抑制和GPR 119的基因敲除（通过双敲除）使胃排空缺陷正常化，而双敲除小鼠在体重、肥胖或食物摄入方面没有表现出差异。第三，胃排空减少依赖于肽YY（PYY）和GLP-1信号传导的组合，重要的是，作者证明这可能是GPR 119激活的下游，因为双敲除小鼠（GPR 119和Cyp 8b 1）消除了禁食-再喂养研究后在Cyp 8b 1-/-小鼠中观察到的回肠PYY和GLP-1水平的增加。因此，该研究得出结论，Cyp 8b 1-/-小鼠的肥胖减少是由于远端小肠脂质的存在增加，可能激活回肠GPR 119-GLP-1和-PYY轴，减缓胃排空以减少肥胖。
The gastrointestinal (GI) tract is increasingly recognised as a major contributor to energy homoeostasis that impact obesity progression. The gut represents the first site of interaction between incoming nutrients and the host, generating crucial negative feedback signalling to regulate food intake possibly by altering GI function like gastric emptying. In the case of proximal intestinal lipid sensing, several mechanisms have been identified to drive both satiety and satiation. For example, dietary fat is hydrolysed and absorbed into enterocytes. In the upper GI, this stimulates the synthesis of oleoylethanolamide (OEA), which can then act as a signalling molecule to induce satiety via activation of peroxisome proliferator-activated receptor-α and a gut-brain axis. 1 Alternatively, activation of enteroendocrine cells (EECs) by free fatty acids binding to G proteincoupled receptor-40 leads to secretion of gut peptides, like cholecystokinin and glucagon-like peptide-1 (GLP-1), which slow gastric emptying and reduce food intake. Interestingly, activation of EECs via free fatty acids is hypothesised to occur on the basolateral side, requiring chylomicron formation, and thus dietary fat hydrolysis, similar to OEA production. 2 Given that bile acids, especially cholic acid in mice, emulsify dietary lipids and thus promote efficient hydrolysis and absorption of lipids in the small intestine, their function would implicate a necessity in activating the aforementioned pathways to lower food intake. In GUT, Higuchi et al observed that Cyp8b1-/-mice exhibited reduced body weight and adiposity due to an inhibition of food intake. As expected, lowering cholic acid and other 12α-hydroxylated bile acids via 12α-hydroxylase Cyp8b1 knockout impairs dietary fat absorption. However, they elegantly deciphered the mechanism explaining the unexpectedly decreased body weight and reduced food intake by identifying that the gastric emptying incurred by a lower intestinal lipid-gut peptide signalling axis. 3 Cyp8b1-/-mice exhibited reduced body weight and adiposity due to an inhibition of food intake. Mechanistically, Cyp8b1-/- mice actually had decreased refed jejunal OEA levels, therefore increased intestinal OEA signalling leading to increased satiety is not the driving mechanism for reduced food intake. This is in line with the fact that Cyp8b1-/- mice exhibited reductions in meal size, and not inter-meal interval, suggesting the decrease in food intake is via increased satiation and not satiety. Instead, the authors attributed the reduction in meal size to slowed gastric emptying. First, the authors established this reduction in gastric emptying was lipid-dependent, as feeding of a fat-free diet abolished the reduced food intake and gastric emptying in Cyp8b1-/-mice. Second, the authors established slowed gastric emptying was mediated via GPR119 signalling, as both acute pharmacological inhibition of GPR119 in Cyp8b1-/-mice and genetic knockout of GPR119 (via double knockout) normalised the gastric emptying defect, while double knockout mice exhibited no difference in body weight, adiposity or food intake. Third, reduced gastric emptying was dependent on a combination of peptide YY (PYY) and GLP-1 signalling, and importantly, the authors demonstrated that this was likely downstream of GPR119 activation, as double knockout mice (GPR119 and Cyp8b1) abolished the increase in ileal PYY and GLP-1 levels observed in Cyp8b1-/-mice following a fasting-refeeding study. Thus, the study concluded that reduced adiposity in Cyp8b1-/- mice is due to increased presence of distal small intestinal lipids, potentially activating an ileal GPR119-GLP-1 and–PYY axis that slows gastric emptying to reduce …
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影响因子：
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DOI：
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