Al-Dwairi Ahmed, Brown Adam R, Pabona John Mark P, Van Trang H, Hamdan Hamdan, Mercado Charles P, Quick Charles M, Wight Patricia A, Simmen Rosalia C M, Simmen Frank A
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
PLoS One. 2014 Nov 17;9(11):e113058. doi: 10.1371/journal.pone.0113058. eCollection 2014.
The small intestine participates in lipid digestion, metabolism and transport. Cytosolic malic enzyme 1 (ME1) is an enzyme that generates NADPH used in fatty acid and cholesterol biosynthesis. Previous work has correlated liver and adipose ME1 expression with susceptibility to obesity and diabetes; however, the contributions of intestine-expressed ME1 to these conditions are unknown. We generated transgenic (Tg) mice expressing rat ME1 in the gastrointestinal epithelium under the control of the murine villin1 promoter/enhancer. Levels of intestinal ME1 protein (endogenous plus transgene) were greater in Tg than wildtype (WT) littermates. Effects of elevated intestinal ME1 on body weight, circulating insulin, select adipocytokines, blood glucose, and metabolism-related genes were examined. Male Tg mice fed a high-fat (HF) diet gained significantly more body weight than WT male littermates and had heavier livers. ME1-Tg mice had deeper intestinal and colon crypts, a greater intestinal 5-bromodeoxyuridine labeling index, and increased expression of intestinal lipogenic (Fasn, Srebf1) and cholesterol biosynthetic (Hmgcsr, Hmgcs1), genes. The livers from HF diet-fed Tg mice also exhibited an induction of cholesterol and lipogenic pathway genes and altered measures (Irs1, Irs2, Prkce) of insulin sensitivity. Results indicate that gastrointestinal ME1 via its influence on intestinal epithelial proliferation, and lipogenic and cholesterologenic genes may concomitantly impact signaling in liver to modify this tissue's metabolic state. Our work highlights a new mouse model to address the role of intestine-expressed ME1 in whole body metabolism, hepatomegaly, and crypt cell proliferation. Intestinal ME1 may thus constitute a therapeutic target to reduce obesity-associated pathologies.
小肠参与脂质的消化、代谢和运输。胞质苹果酸酶1（ME1）是一种可生成用于脂肪酸和胆固醇生物合成的NADPH的酶。先前的研究已将肝脏和脂肪组织中的ME1表达与肥胖症和糖尿病易感性联系起来；然而，肠道表达的ME1对这些病症的作用尚不清楚。我们构建了在小鼠绒毛蛋白1启动子/增强子控制下在胃肠道上皮中表达大鼠ME1的转基因（Tg）小鼠。Tg小鼠肠道ME1蛋白（内源性加转基因）水平高于野生型（WT）同窝小鼠。研究了肠道ME1升高对体重、循环胰岛素、选定的脂肪细胞因子、血糖和代谢相关基因的影响。喂食高脂（HF）饮食的雄性Tg小鼠比WT雄性同窝小鼠体重显著增加，肝脏更重。ME1-Tg小鼠的肠隐窝和结肠隐窝更深，肠道5-溴脱氧尿苷标记指数更高，肠道生脂（Fasn、Srebf1）和胆固醇生物合成（Hmgcsr、Hmgcs1）基因的表达增加。喂食HF饮食的Tg小鼠的肝脏也表现出胆固醇和生脂途径基因的诱导以及胰岛素敏感性的改变（Irs1、Irs2、Prkce）。结果表明，胃肠道ME1通过其对肠上皮增殖以及生脂和胆固醇生成基因的影响，可能同时影响肝脏中的信号传导，从而改变该组织的代谢状态。我们的工作突出了一种新的小鼠模型，用于研究肠道表达的ME1在全身代谢、肝肿大和隐窝细胞增殖中的作用。因此，肠道ME1可能构成一个治疗靶点，以减少与肥胖相关的病理状况。
