MICA: Targeting glucose metabolism in Nonalcoholic fatty liver disease

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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.