MICA: Targeting glucose metabolism in Nonalcoholic fatty liver disease

我们建议通过靶向肝脏葡萄糖磷酸化来识别抑制肝脏葡萄糖清除的小分子。假设肝脏脂肪变性、血甘油三酯升高和脂肪变性进展为NASH和纤维化分别是由于饮食中碳水化合物过量引起的肝脏高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所致。我们认为抑制肝脏葡萄糖清除可以通过抑制肝脏葡萄糖激酶(GK)来实现。因为抑制胰腺葡萄糖激酶会导致高血糖，就像GCK突变一样。目的是实现对肝脏GK的选择性靶向。要做到这一点，主要的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，并通过与葡萄糖激酶的高亲和力来稳定其构象状态，类似于果糖6-磷酸或山梨醇6-磷酸诱导的构象状态，从而起到“GK-GKRP增强剂”的作用。这样的分子会增加葡萄糖激酶在与GKRP结合的细胞核中的滞留。

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.