Zhu Lixin, Baker Susan S, Shahein Abdul, Choudhury Shelly, Liu Wensheng, Bhatia Tavleen, Baker Robert D, Lee Techung
Department of Biochemistry and Department of Pediatrics, University at Buffalo, 955 Main Street, Buffalo, NY 14203.
Trends Cell Mol Biol. 2018;13:47-56.
Wnt ligands regulate metabolic pathways, and dysregulation of Wnt signaling contributes to chronic inflammatory disease. A knowledge gap exists concerning the role of aberrant Wnt signaling in non-alcoholic steatohepatitis (NASH), which exhibits metabolic syndrome and inflammation. Using a mouse model of methionine-choline deficient diet (MCDD)-induced NASH, we investigated the Wnt signaling pathways in relation to hepatic glucose oxidation. Mice fed the MCD diet for 6 weeks developed prominent NASH marked by macrovesicular steatosis, inflammation and lipid peroxidation. qPCR analysis reveals differential hepatic expression of canonical and non-canonical Wnt ligands. While expression of Wnt3a was decreased in NASH vs chow diet control, expression of Wnt5a and Wnt11 were increased 3 fold and 15 fold, respectively. Consistent with activation of non-canonical Wnt signaling, expression of the alternative Wnt receptor ROR2 was increased 5 fold with no change in LRP6 expression. Activities of the metabolic enzymes glucokinase, phosphoglucoisomerase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, and pyruvate dehydrogenase were all elevated by MCDD. NASH-driven glucose oxidation was accompanied by a 6-fold increase in lactate dehydrogenase (LDH)-B with no change in LDH-A. In addition, glucose-6-phosphate dehydrogenase, the regulatory and NADPH-producing enzyme of the pentose phosphate pathway, was elevated in NASH. These data support a role of accelerated glucose oxidation in the development of NASH, which may be driven by non-canonical Wnt signaling.
Wnt配体调节代谢途径，Wnt信号失调会导致慢性炎症性疾病。关于异常Wnt信号在非酒精性脂肪性肝炎（NASH）中的作用存在知识空白，NASH表现出代谢综合征和炎症。我们使用蛋氨酸-胆碱缺乏饮食（MCDD）诱导的NASH小鼠模型，研究了与肝脏葡萄糖氧化相关的Wnt信号通路。喂食MCD饮食6周的小鼠出现了以大泡性脂肪变性、炎症和脂质过氧化为特征的明显NASH。qPCR分析揭示了经典和非经典Wnt配体在肝脏中的差异表达。与对照的正常饮食相比，NASH中Wnt3a的表达降低，而Wnt5a和Wnt11的表达分别增加了3倍和15倍。与非经典Wnt信号的激活一致，替代Wnt受体ROR2的表达增加了5倍，而LRP6的表达没有变化。MCDD使代谢酶葡萄糖激酶、磷酸葡萄糖异构酶、甘油醛-3-磷酸脱氢酶、丙酮酸激酶和丙酮酸脱氢酶的活性均升高。NASH驱动的葡萄糖氧化伴随着乳酸脱氢酶（LDH）-B增加6倍，而LDH-A没有变化。此外，戊糖磷酸途径的调节酶和产生NADPH的葡萄糖-6-磷酸脱氢酶在NASH中升高。这些数据支持加速葡萄糖氧化在NASH发展中的作用，这可能由非经典Wnt信号驱动。
