title: Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans.
abstract: OBJECTIVE
  Glucokinase (GCK) phosphorylates glucose to form glucose 6-phosphate and thereby regulates hepatic glucose disposal and activates hepatic lipogenesis. Hepatic GCK activity is regulated on the level of GCK mRNA expression and by the inhibitory glucokinase regulatory protein. In this study, we aimed to investigate the relation between GCK mRNA expression and markers of lipogenesis as well as liver fat content in human liver biopsies. Additionally, we investigated whether genetic variation in the liver specific GCK promoter determines liver fat content in humans.
  
  
  METHODS
  Hepatic mRNA expression and liver triglyceride content was analyzed in 50 human liver biopsies. In a second cohort of 330 individuals, liver fat was precisely measured by 1H magnetic resonance spectroscopy.
  
  
  RESULTS
  Hepatic GCK mRNA expression is associated with triglyceride content in human liver biopsies (r = 0.50, P = 0.0002). Furthermore, hepatic GCK mRNA expression is associated with lipogenic gene expression (fatty acid synthase, r = 0.49, P = 0.0003; acetyl-coenzyme A carboxylase-α, r = 0.44, P = 0.0015, and acetyl-coenzyme A carboxylase-β, r = 0.48, P = 0.0004) and the de novo lipogenesis index (r = 0.36, P = 0.01). In support of these findings, the single-nucleotide polymorphism rs2041547 in the liver-specific GCK promoter is associated with liver fat content in prediabetic individuals (P = 0.047).
  
  
  CONCLUSIONS
  In this study, we demonstrate for the first time that GCK mRNA expression is associated with markers of de novo lipogenesis and liver triglyceride content in humans. This suggests that increased GCK activity may induce fatty liver and its metabolic and hepatic consequences in humans. Thus, the widely used approach to nonspecifically activate β-cell and hepatic GCK to treat diabetes mellitus is therefore questionable and may cause serious side effects.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Tübingen, 72076 Tübingen, Germany. andreas.peter@med.uni-tuebingen.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Alexander
authors.initials: A
authors.lastname: Cegan
authors.forename: Mareike
authors.initials: M
authors.lastname: Walenta
authors.forename: Silvia
authors.initials: S
authors.lastname: Wagner
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.forename: Ingmar
authors.initials: I
authors.lastname: Königsrainer
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D005941:Glucokinase