Available online 7 April 2023, 101722

P446>L substitution in mouse or human GKRP compromises GKRP stability and GK binding (84).

The GKRP:P446L mouse has low liver GKRP and glucokinase similar to rs1260326-TT liver (85).

The GKRP:P446L mouse manifests low blood glucose and insulin similar to rs160326-TT (83).

The diet-challenged GKRP:P446L mouse has high blood cholesterol but not triglyceride (84).

The GKRP:P446L mouse replicates the raised blood cholesterol linked to rs1260326(C>T) (85).

The Glucokinase Regulatory Protein GKRP, encoded by GCKR, enables acute regulation of liver glucokinase to support metabolic demand. The common human GCKR rs1260326:P446>L variant within a large linkage disequilibrium region associates with pleiotropic traits, lower Type 2 diabetes risk and raised blood triglycerides and cholesterol. Whether GCKR-P446>L is causal to the raised lipids is unknown. We determined whether mouse GKRP phenocopies human GKRP:P446>L and studied a GKRP:P446L mouse to identify physiological consequences to P446>L.

GKRP-deficient hepatocytes were transfected with adenoviral vectors for human or mouse GKRP:446P or 446L for cellular comprehensive analysis including transcriptomics consequent to P446>L. Physiological traits in the diet-challenged P446L mouse were compared with pleiotropic associations at the human rs1260326 locus. Transcriptomics was compared in P446L mouse liver with hepatocytes expressing glucokinase or GKRP:446P/L.

1. P446>L substitution in mouse or human GKRP similarly compromises protein expressivity of GKRP:446L, nuclear sequestration of glucokinase and counter-regulation of gene expression. 2. The P446L knockin mouse has lower liver glucokinase and GKRP protein similar to human liver homozygous for rs1260326-446L. 3. The diet-challenged P446L mouse has lower blood glucose, raised blood cholesterol and altered hepatic cholesterol homeostasis consistent with relative glucokinase-to-GKRP excess, but not raised blood triglycerides.

Mouse GKRP phenocopies the human GKRP:P446>L substitution despite the higher affinity for glucokinase of human GKRP. The diet-challenged P446L mouse replicates several traits found in association with the rs1260326 locus on chromosome 2 including raised blood cholesterol, lower blood glucose and lower liver glucokinase and GKRP protein.

Liver

glucose metabolism

glucokinase

Type 2 diabetes

fatty liver

blood cholesterol

Differentially expressed genes

glucokinase overexpression

glucokinase regulatory protein

high-fat high-sugar diet

nonalcoholic fatty liver disease

non-alcoholic steatohepatitis

nuclear / cytoplasmic ratio

© 2023 The Author(s). Published by Elsevier GmbH.