Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203; King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Eastern Region, Ministry of National Guard Health Affairs, Al Ahsa 31982, Saudi Arabia.
Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203.
J Biol Chem. 2020 Mar 27;295(13):4101-4113. doi: 10.1074/jbc.RA119.011881. Epub 2020 Feb 11.
The hormone leptin regulates fat storage and metabolism by signaling through the brain and peripheral tissues. Lipids delivered to peripheral tissues originate mostly from the intestine and liver via synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins. An intracellular chaperone, microsomal triglyceride transfer protein (MTP), is required for the biosynthesis of these lipoproteins, and its regulation determines fat mobilization to different tissues. Using cell culture and animal models, here we sought to identify the effects of leptin on MTP expression in the intestine and liver. Leptin decreased MTP expression in differentiated intestinal Caco-2 cells, but increased expression in hepatic Huh7 cells. Similarly, acute and chronic leptin treatment of chow diet-fed WT mice decreased MTP expression in the intestine, increased it in the liver, and lowered plasma triglyceride levels. These leptin effects required the presence of leptin receptors (LEPRs). Further experiments also suggested that leptin interacted with long-form LEPR (ObRb), highly expressed in the intestine, to down-regulate MTP. In contrast, in the liver, leptin interacted with short-form LEPR (ObRa) to increase MTP expression. Mechanistic experiments disclosed that leptin activates signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling pathways in intestinal and hepatic cells, respectively, and thereby regulates divergent MTP expression. Our results also indicated that leptin-mediated MTP regulation in the intestine affects plasma lipid levels. In summary, our findings suggest that leptin regulates MTP expression differentially by engaging with different LEPR types and activating distinct signaling pathways in intestinal and hepatic cells.
瘦素通过大脑和外周组织信号通路调节脂肪储存和代谢。输送到外周组织的脂质主要来源于肠道和肝脏，通过合成和分泌载脂蛋白 B（apoB）的脂蛋白。一种细胞内伴侣蛋白，微粒体甘油三酯转移蛋白（MTP），是这些脂蛋白生物合成所必需的，其调节决定了脂肪向不同组织的动员。通过细胞培养和动物模型，我们试图确定瘦素对肠道和肝脏中 MTP 表达的影响。瘦素降低了分化的肠道 Caco-2 细胞中 MTP 的表达，但增加了肝 Huh7 细胞中 MTP 的表达。同样，急性和慢性给予瘦素治疗正常饮食喂养的 WT 小鼠，降低了肠道中 MTP 的表达，增加了肝脏中的 MTP 表达，并降低了血浆甘油三酯水平。这些瘦素作用需要瘦素受体（LEPRs）的存在。进一步的实验还表明，瘦素与长型 LEPR（ObRb）相互作用，ObRb 在肠道中高度表达，从而下调 MTP。相比之下，在肝脏中，瘦素与短型 LEPR（ObRa）相互作用，增加 MTP 的表达。机制实验揭示了瘦素分别在肠道和肝细 胞中激活信号转导和转录激活因子 3（STAT3）和丝裂原活化蛋白激酶（MAPK）信号通路，从而调节不同的 MTP 表达。我们的研究结果还表明，瘦素在肠道中调节 MTP 的表达会影响血浆脂质水平。总之，我们的研究结果表明，瘦素通过与不同的 LEPR 类型结合并在肠道和肝细 胞中激活不同的信号通路，来调节 MTP 的表达。
