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MolMet Figure 3: Lower GKRP and GK protein levels in human NAFLD biopsies of the rs1260326-TT genotype and in the P446L mouse.

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posted on 2023-04-19, 15:48 authored by Brian FordBrian Ford, Loranne AgiusLoranne Agius

A-I) Human NAFLD biopsies genotyped for GCKR rs1260326 variant (CC n=23; TT n=17) and scored as simple steatosis (NAFL) or NASH were stained for GKRP or GK and nuclear (N-H) and cytoplasmic (C-H) H-scores were determined. (A) representative images.

(B-D) Lower GKRP N-H scores by TT genotype for entire cohort (B) or by -/+ NASH diagnosis (C), lower C-H scores (D)

(E-G) Lower GK N-H scores by TT genotype for entire cohort (E) or by -/+ NASH diagnosis (F) and lower C-H scores (G)

H) Correlation of GK N-H vs GKRP N-H, r2 0.34, P<0.0001 for entire data set.

I) Lower GK (N-H) / GKRP (N-H) ratio by TT genotype, # P< 0.0003.

J-M) GKRP P446L mouse aged 14-wk (regular diet, n=4,4, PP, LL) or 28-wk (on HFHSD for last 20-wk, n=10,10, PP, LL): Liver Gckr and Gck mRNA normalized to RplpO (J); GKRP and GK protein (K-L) and GK enzyme activity (M).

J) Similar Gckr mRNA by genotype but lower Gck mRNA in 28-wk mice by LL genotype.

K-L) Lower GKRP and GK immunoactive protein (n=4-8) and lower GK activity (M, n=4,4,10,10,10) by LL genotype. #P<0.05, LL vs PP; *P<0.05 28-wk vs 14 wk.

N-R) Comparative GKRP and GK immunostaining of human liver biopsies (CC,TT: n=7,6) and P446L mouse liver (PP, PL, LL: n=7,4,5) showing representative images for mouse (N) and the N-H and C-H scores.

O) Lower GKRP N-H scores for human compared with mouse ($) liver and by TT and LL genotypes (#) and negligible cytoplasmic H-scores.

P) Lower GK N-H and C-H for human compared with mouse liver ($) and lower N-H by TT (human) or LL (mouse) genotype (#).

Q) Correlation of GK and GKRP N-H scores.

R) Relative distribution of GK in nucleus and cytoplasm (N-H/C-H ratio) showing lower nuclear GK sequestration by TT and LL genotypes. #P<0.05 by genotype; $P<0.05 human vs. mouse.

Funding

MICA: Exploring a new perspective on the mechanism of action of Glucokinase Activators in liver, a preclinical study

Medical Research Council

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