Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans.

Abstract

BACKGROUND/AIMS:

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: Andreas Peter, Norbert Stefan, Alexander Cegan, Mareike Walenta, Silvia Wagner, Alfred Königsrainer, Ingmar Königsrainer, Fausto Machicao, Fritz Schick, Hans-Ulrich Häring, Erwin Schleicher
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 96 Issue 7 Pg. E1126-30 (Jul 2011) ISSN: 1945-7197 [Electronic] United States
• PMID: 21490074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Glucokinase

Topics

• Adolescent
• Adult
• Aged
• Alleles
• Fatty Liver (genetics, metabolism)
• Female
• Glucokinase (genetics, metabolism)
• Humans
• Lipogenesis (physiology)
• Liver (metabolism)
• Male
• Middle Aged
• RNA, Messenger (genetics, metabolism)