AIM: Alpha2-Heremans Schmid
glycoprotein (
AHSG), also known as fetuin-A, is
secreted from the
liver and inhibits
tyrosine kinase activity of the
insulin receptor.
Hyperglycemia in
type 2 diabetes is not only a secondary manifestation of
insulin resistance, but could also be responsible for directly inducing
insulin resistance in target tissues. In this study, we examined the effect of high
glucose (HG) on
AHSG gene transcription in the human
hepatoma cell line HepG2. METHODS:
AHSG transcriptional activity and
protein expression were evaluated using
reporter gene assays and
Western blot analysis, respectively. RESULTS:
D-glucose, but not L-glucose or
mannitol, dose-dependently enhanced
AHSG promoter activity. HG (25 mM) also increased
AHSG protein expression. No
protein kinase C inhibitors (bisindolylmaleimide, Ro-31-8220), an inhibitor of
hexosamine biosynthesis pathway (6-diazo-5-oxo-L-norleucine), or a
superoxide radical scavenger (tempol) affected HG-induced transactivation.
MAPK/ERK kinase inhibitors (PD98059,
U0126), but not the
JNK inhibitor (SP600125) or p38 inhibitor (SB203580), significantly inhibited
promoter activation by HG. CONCLUSION: Our data suggest that HG enhances
AHSG transcription through
activation of the
ERK1/2
signaling pathway. Increased
AHSG expression in the
liver may be a cause of
glucose toxicity in the
diabetic state.
