Glucokinase Inactivation Ameliorates Lipid Accumulation and Exerts Favorable Effects on Lipid Metabolism in Hepatocytes

Abstract

Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a kind of rare diabetes with low incidence of vascular complications caused by GCK gene inactivation. This study aimed to investigate the effects of GCK inactivation on hepatic lipid metabolism and inflammation, providing evidence for the cardioprotective mechanism in GCK-MODY. We enrolled GCK-MODY, type 1 and 2 diabetes patients to analyze their lipid profiles, and found that GCK-MODY individuals exhibited cardioprotective lipid profile with lower triacylglycerol and elevated HDL-c. To further explore the effects of GCK inactivation on hepatic lipid metabolism, GCK knockdown HepG2 and AML-12 cell models were established, and in vitro studies showed that GCK knockdown alleviated lipid accumulation and decreased the expression of inflammation-related genes under fatty acid treatment. Lipidomic analysis indicated that the partial inhibition of GCK altered the levels of several lipid species with decreased saturated fatty acids and glycerolipids including triacylglycerol and diacylglycerol, and increased phosphatidylcholine in HepG2 cells. The hepatic lipid metabolism altered by GCK inactivation was regulated by the enzymes involved in de novo lipogenesis, lipolysis, fatty acid β-oxidation and the Kennedy pathway. Finally, we concluded that partial inactivation of GCK exhibited beneficial effects in hepatic lipid metabolism and inflammation, which potentially underlies the protective lipid profile and low cardiovascular risks in GCK-MODY patients.

A comprehensive review on the potential therapeutic benefits of prospective probiotic Christensenella minuta

“…Mazier et al [15] found that C. minuta DSM33407 suppressed hepatic lipid accumulation in high-fat diet-fed animals in association with strong repression of the Glucokinase (Gck) gene. Gck inhibition ameliorates hepatic lipid accumulation and inflammation by altering the expression of genes involved in adipogenesis, lipolysis and β-oxidation in the liver [78] . Claudin-1 (Cldn1), Occludin (Ocln), Zonula Occludens-1 (Zo1) is required for the maintenance of a functional intestinal barrier [79] .…”

Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD

“…Given the adverse consequences of over-activation of hepatic GK, some researchers have proposed that inhibiting hepatic GK may have potential metabolic benefits ( 146 , 147 ). However, more important is how to strike a balance between the activation and inhibition.…”

G-quadruplex forming regions inGCKandTM6SF2are targets for differential DNA methylation in metabolic disease and hepatocellular carcinoma patients

“…To investigate the link between differential DNA methylation and non-B DNA formation in MetDs, we performed locus-specific 5mC analysis in the gene body of two key metabolic genes, exon 7 of glucokinase (GCK) and the intron 2-exon 3 boundary of transmembrane 6 superfamily 2 (TM6SF2) using 148 blood samples from a well-characterized cohort including lean and obese healthy subjects, lean and obese MAFLD, and patients suffering from advanced MetDs including uncontrolled T2DM and severe MAFLD, collected at the University Hospital Salzburg, Austria. GCK and TM6SF2 are not only known risk genes (GCK (40)(41)(42)(43), TM6SF2 (44)(45)(46)(47)(48)), but are also targets for drug design (49). In this study, we focused on intragenic regions overlapped by long non-coding RNAs, which potentially form R-loops in these genes and enhance G4 formation.…”