MRC/AZ CLD 2018

Lead Research Organisation: Newcastle University

Abstract

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.

Technical Summary

Nonalcoholic fatty liver disease (NAFLD) is the fastest growing cause of liver disease globally, it increases the risk of mortality from liver and cardiovascular disease. Its prevalence is linked to obesity, hyperlipidaemia and dietary carbohydrate excess and it is present in 80% of obese individuals with an overall prevalence of 25%. NAFLD covers a range of conditions from hepatic triglyceride accumulation (steatosis) to inflammation (non-alcoholic steatohepatitis, NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although liver steatosis was considered to be benign, this dogma has been challenged because of disease progression from steatosis to NASH and fibrosis. There are no approved pharmacotherapies for NAFLD. The purpose of this project is to identify small molecules that inhibit liver glucose phosphorylation by promoting increased binding of glucokinase to its regulatory protein, GKRP. The hypothesis is that inhibiting the first regulated step of hepatic glucose clearance protects the liver from glucose overload and attenuates hepatic production of triglycerides which contributes to both steatosis and raised blood triglycerides. The merits of this strategy are that it does not predispose to elevation of intrahepatic metabolites with consequent compensatory changes in gene expression, as occurs by selective activation of the first regulated step or targeting of downstream sites[2]. The rationale for the strategy is supported by sets of evidence. First, common single nucleotide polymorphisms in the GCKR gene encoding variant GKRP with decreased affinity for glucokinase associate with raised blood lipids and NAFLD steatosis and disease progression to NASH and fibrosis. Second, inactivating mutations in the GCK gene in man which predict a decreased glucose phosphorylation capacity associate with lower blood triglycerides. We will use novel transgenic Gckr mouse models to validate the identified hits and test proof-of-concept

Planned Impact

Nonalcoholic fatty liver disease (NAFLD) is the fastest growing cause of liver disease globally, it increases the risk of mortality from liver and cardiovascular disease. Its prevalence is linked to obesity, hyperlipidaemia and dietary carbohydrate excess and it is present in 80% of obese individuals with an overall prevalence of 25%[1]. NAFLD covers a range of conditions from hepatic triglyceride accumulation (steatosis) to inflammation (non-alcoholic steatohepatitis, NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although liver steatosis was considered to be benign, this dogma has been challenged because of disease progression from steatosis to NASH and fibrosis. There are no approved pharmacotherapies for NAFLD. The purpose of this project is to identify small molecules that inhibit liver glucose phosphorylation by promoting increased binding of glucokinase to its regulatory protein, GKRP. The hypothesis is that inhibiting the first regulated step of hepatic glucose clearance protects the liver from glucose overload and attenuates hepatic production of triglycerides which contributes to both steatosis and raised blood triglycerides. The merits of this strategy are that it does not predispose to elevation of intrahepatic metabolites with consequent compensatory changes in gene expression, as occurs by selective activation of the first regulated step or targeting of downstream sites[2]. The rationale for the strategy is supported by sets of evidence. First, common single nucleotide polymorphisms in the GCKR gene encoding variant GKRP with decreased affinity for glucokinase associate with raised blood lipids and NAFLD steatosis and disease progression to NASH and fibrosis[2,3]. Second, inactivating mutations in the GCK gene in man which predict a decreased glucose phosphorylation capacity associate with lower blood triglycerides[4]. We will use novel transgenic Gckr mouse models to validate the identified hits and test proof-of-concept.

Publications

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