Ileal interposition surgery targets the hepatic TGF-β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD-T2DM rat model of diabetes.
Ileal interposition surgery targets the hepatic TGF-β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD-T2DM rat model of diabetes.
复制标题
回肠介入手术针对肝脏 TGF-β 途径，影响 UCD-T2DM 糖尿病大鼠模型中的糖异生和线粒体生物能学。
DOI：
10.1096/fj.201802714r
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Giulivi,Cecilia
中科院分区：
文献类型：
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作者：
Hung,Connie;Napoli,Eleonora;Ross-Inta,Catherine;Graham,James;Flores-Torres,AmandaL;Stanhope,KimberL;Froment,Pascal;Havel,PeterJ;Giulivi,Cecilia
回肠介入（IT）是一种外科手术，增加未完全消化的营养物质和胆道和胰腺分泌物到远端肠粘膜的输送。在这里，我们通过评估it手术后1.5个月肝脏基因表达，研究了这种干预对2岁前驱糖尿病大鼠的代谢影响。通路分析表明，通过TGF-β/Smad（一个名为母亲的蛋白质家族）、过氧化物酶体增殖激活受体（PPAR）和雷帕霉素的pi3k - akt - ampk机制靶点的信号传导减少，可能针对肝星状细胞，因为这些细胞的分化和激活与通过PPAR和TGF-β/Smad的信号传导减少有关。IT手术上调了参与胆固醇和萜类合成调控的基因表达，下调了参与甘油磷脂代谢（包括心磷脂）、脂肪生成和糖异生的基因表达。与肝脏CL通路下调一致，IT手术在肝脏、肾脏皮质和脂肪库中产生代谢开关，使线粒体脂肪酸β-氧化减少，这一过程需要为高能量需求通路（如糖异生和甘油生成）提供燃料，而在骨骼肌和心肌中观察到相反的效果。这项研究首次证明了代谢途径的存在，补充了IT手术的效果，以最大限度地发挥其益处，并有可能确定类似有效、持久、侵入性较小的代谢性疾病治疗选择，包括TGF-β信号的抑制剂。-Hung， C, Napoli， E., Ross-Inta， C., Graham， J., Flores-Torres， A. L., Stanhope， K. L., Froment， P., Havel， P. J., Giulivi， C.回肠介入手术靶向肝脏TGF-β通路，影响UCD-T2DM模型大鼠的糖异生和线粒体生物能量学。
Ileal interposition (IT) is a surgical procedure that increases the delivery of incompletely digested nutrients and biliary and pancreatic secretions to the distal intestinal mucosa. Here, we investigated the metabolic impact of this intervention in 2-mo-old prediabetic University of California, Davis type 2 diabetes mellitus rats by assessing liver gene expression at 1.5 mo post-IT surgery. Pathway analysis indicated decreased signaling via TGF-β/Smad (a family of proteins named mothers against decapentaplegic homologs), peroxisome proliferator-activated receptor (PPAR), and PI3K-Akt-AMPK–mechanistic target of rapamycin, likely targeting hepatic stellate cells because differentiation and activation of these cells is associated with decreased signaling via PPAR and TGF-β/Smad. IT surgery up-regulated the expression of genes involved in regulation of cholesterol and terpenoid syntheses and down-regulated those involved in glycerophospholipid metabolism [including cardiolipin (CL)], lipogenesis, and gluconeogenesis. Consistent with the down-regulation of the hepatic CL pathway, IT surgery produced a metabolic switch in liver, kidney cortex, and fat depots toward decreased mitochondrial fatty acid β-oxidation, the process required to fuel high energy–demanding pathways (e.g., gluconeogenesis and glyceroneogenesis), whereas opposite effects were observed in skeletal and cardiac muscles. This study demonstrates for the first time the presence of metabolic pathways that complement the effects of IT surgery to maximize its benefits and potentially identify similarly effective, durable, and less invasive therapeutic options for metabolic disease, including inhibitors of TGF-β signaling.—Hung, C., Napoli, E., Ross-Inta, C., Graham, J., Flores-Torres, A. L., Stanhope, K. L., Froment, P., Havel, P. J., Giulivi, C. Ileal interposition surgery targets the hepatic TGF-β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD-T2DM rat model of diabetes.