Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Physiol Gastrointest Liver Physiol. 2020 Apr 1;318(4):G682-G693. doi: 10.1152/ajpgi.00386.2018. Epub 2020 Jan 31.
Postprandial dyslipidemia is a common feature of insulin-resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. Although bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here, we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions, and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA (but not DCA) effects were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the antidiabetic hormone glucagon-like peptide-1 (GLP-1). Although the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate-limiting enzyme for bile acid synthesis. Bile acid signaling may be an important mechanism of controlling dietary lipid absorption, and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia. We present new data suggesting potentially important roles for bile acids in regulation of postprandial lipid metabolism. Specific bile acid species, particularly secondary bile acids, were found to markedly inhibit absorption of dietary lipid and reduce postprandial triglyceride excursion. These effects appear to be mediated via bile acid receptors, farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Importantly, bile acid signaling may trigger glucagon-like peptide-1 (GLP-1) secretion, which may in turn mediate the marked inhibitory effects on dietary fat absorption.
餐后血脂异常是胰岛素抵抗状态的一个常见特征，增加了心血管疾病的风险。最近，胆汁酸除了具有乳化特性外，还被认为是促进能量消耗、改善胰岛素敏感性和降低空腹血脂的重要信号分子。尽管胆汁酸受体已成为新的药物靶点，但它们对餐后脂质代谢的影响尚不清楚。在这里，我们研究了胆汁酸在调节餐后乳糜微粒生成和甘油三酯波动中的潜在作用。在高脂肪负荷条件下，将牛磺胆酸（TA）十二指肠内输注给健康 C57BL/6 小鼠，并测量循环脂质。使用合成的法尼醇 X 受体（FXR）激动剂 GW4064 和 Takeda G 蛋白偶联受体 5 的激动剂脱氧胆酸（DCA）靶向胆汁酸受体。TA、GW4064 和 DCA 处理均降低了餐后血脂。FXR 激动剂还降低了肠道甘油三酯含量和参与乳糜微粒组装的微粒体甘油三酯转移蛋白的活性。重要的是，在 FXR 敲除小鼠中，TA（但不是 DCA）的作用大部分丧失。这些胆汁酸作用类似于抗糖尿病激素胰高血糖素样肽-1（GLP-1）。尽管 GLP-1 受体激动剂 exendin-4 在胆汁酸螯合和 FXR 缺乏期间仍然能够急性降低餐后血脂，但它确实提高了胆汁酸合成限速酶的肝表达。胆汁酸信号可能是控制膳食脂质吸收的重要机制，胆汁酸受体可能是治疗餐后血脂异常的新靶点。我们提供了新的数据，表明胆汁酸在调节餐后脂质代谢中可能具有重要作用。发现特定的胆汁酸种类，特别是次级胆汁酸，明显抑制膳食脂质的吸收并降低餐后甘油三酯波动。这些作用似乎是通过胆汁酸受体、法尼醇 X 受体（FXR）和 Takeda G 蛋白偶联受体 5（TGR5）介导的。重要的是，胆汁酸信号可能触发胰高血糖素样肽-1（GLP-1）的分泌，这反过来可能介导对膳食脂肪吸收的显著抑制作用。
