MICA: Targeting glucose metabolism in Nonalcoholic fatty liver disease

MICA：针对非酒精性脂肪肝疾病的葡萄糖代谢

• 批准号: MC_EX_MR/R02345X/1
• 负责人: Loranne Agius
• 金额: $ 3.09万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FR02345X%2F1
• 关键词: MICA; Targeting; glucose; metabolism; Nonalcoholic

We propose to identify small molecules that inhibit hepatic glucose clearance by targeting hepatic glucose phosphorylation. The hypothesis is that hepatic steatosis, raised blood triglycerides and progression of steatosis to NASH and fibrosis is caused by high hepatic glucose disposal resulting from dietary carbohydrate excess and elevated glucokinase expression or activity consequent to hyperinsulinaemia or genetic variants, respectively. We envisage inhibition of hepatic glucose clearance could be achieved by inhibiting liver glucokinase (GK). Because inhibition of pancreatic glucokinase would lead to hyperglycaemia as occurs with GCK mutations. the objective is to achieve selective targeting for hepatic GK. The primary approach to this will be to identify small molecules that bind to the glucokinase regulatory protein (GKRP encoded by the GCKR gene), and stabilize its conformational state with high-affinity for glucokinase, similar to that induced by fructose 6-phosphate or sorbitol 6-phosphate thereby functioning as "GK-GKRP enhancers". Such molecules would increase sequestration of glucokinase in the nucleus bound to GKRP.

我们建议通过靶向肝葡萄糖磷酸化来鉴定抑制肝葡萄糖清除的小分子。假设肝脂肪变性、血甘油三酯升高以及脂肪变性进展为NASH和纤维化分别是由饮食碳水化合物过量导致的高肝葡萄糖处置和高胰岛素血症或遗传变异导致的葡萄糖激酶表达或活性升高引起的。我们设想通过抑制肝葡萄糖激酶（GK）来抑制肝葡萄糖清除。因为胰葡萄糖激酶的抑制会导致高血糖症，就像GCK突变一样。目的是实现肝GK的选择性靶向。对此的主要方法将是鉴定与葡糖激酶调节蛋白（由GCKR基因编码的GKRP）结合的小分子，并以对葡糖激酶的高亲和力稳定其构象状态，类似于由果糖6-磷酸或山梨糖醇6-磷酸诱导的构象状态，从而起到“GK-GKRP增强剂”的作用。这样的分子将增加与GKRP结合的细胞核中葡萄糖激酶的螯合。