Leveraging glucose transport and the adaptive fasting response to modulate hepatic metabolism

非酒精性脂肪性肝病（NAFLD）是一种常见的病态代谢性疾病，可独立预测2型糖尿病及其心血管、肾脏和视网膜并发症的发展。超过10亿人患有NAFLD，使其成为世界上最常见的慢性肝病。有效治疗和预防这种疾病及其并发症的障碍是缺乏有效的NAFLD治疗。我们的长期目标是了解导致NAFLD的潜在葡萄糖代谢途径，这样我们就可以精确地调节这些途径来治疗或预防其进展。我们确定肝脏碳水化合物载体GLUT8作为治疗靶点，因为：(1)GLUT8促进饮食诱导的肝脂肪变性和代谢综合征，（ii）双糖和葡萄糖模拟海藻糖抑制GLUT8并激活适应性禁食反应（例如AMP激酶和自噬），以逆转肝脂肪变性。目的是确定肝细胞葡萄糖转运、海藻糖和适应性肝细胞禁食反应之间的相互作用。我们的初步数据表明，急性肝细胞选择性GLUT8敲低和肝细胞特异性种系GLUT8基因缺失（GLUT8 LKO小鼠）均可诱导肝细胞禁食信号和外周产热。因此，我们假设遗传和药理学肝细胞GLUT8阻断诱导产热并赋予肝脂肪变性抵抗。两个具体目标是：1)确定GLUT8调节肝脏和肝外代谢的机制；2)确定海藻糖诱导的产热和NAFLD保护的机制。我们将通过利用新的实验小鼠模型和独特的体内成像技术来实现这些目标。完成这些目标告诉我们如何最佳地靶向肝细胞葡萄糖转运来增强肝细胞和整个生物体的能量稳态。

Non-alcoholic fatty liver disease (NAFLD) is a common and morbid metabolic disease that independently predicts development of type 2 diabetes mellitus and its cardiovascular, renal and retinal complications. More than one billion individuals have NAFLD, making this the most common chronic liver disease worldwide. A barrier to effectively treating and preventing this disease and its complications is the lack of effective NAFLD treatments. Our long-term goal is to understand the underlying glucose metabolic pathways that lead to NAFLD, so that we can precisely modulate these pathways to treat or prevent its progression. We identified the hepatic carbohydrate carrier, GLUT8, as a therapeutic target because: (i.) GLUT8 promotes diet-induced hepatic steatosis and metabolic syndrome and (ii.) the disaccharide and glucose mimetic trehalose inhibits GLUT8 and activates an adaptive fasting response (e.g. AMP kinase and autophagy), to reverse hepatic steatosis. The objective here is to define the interaction between hepatocyte glucose transport, trehalose, and adaptive hepatocyte fasting responses. Our preliminary data suggest that acute hepatocyte-selective GLUT8 knockdown and hepatocyte- specific germline GLUT8 gene deletion (GLUT8 LKO mice) each induce hepatocyte fasting signals and peripheral thermogenesis. We therefore hypothesize that genetic and pharmacological hepatocyte GLUT8 blockade induces thermogenesis and confers resistance to hepatic steatosis. The two Specific Aims are to 1) Identify mechanisms by which GLUT8 regulates hepatic and extrahepatic metabolism, and 2) Define mechanisms mediating trehalose-induced thermogenesis and protection from NAFLD. We will accomplish these aims by leveraging novel experimental mouse models and unique in vivo imaging techniques. Completing these aims informs how to optimally target hepatocyte glucose transport to augment hepatocyte and whole-organism energy homeostasis.