High glucose induces transactivation of the alpha2-HS glycoprotein gene through the ERK1/2 signaling pathway.
OBJECTIVE
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.


CONCLUSIONS
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.
Takata
Hiroshi
H
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kochi, Japan.
Ikeda
Yukio
Y
Suehiro
Tadashi
T
Ishibashi
Ayako
A
Inoue
Mari
M
Kumon
Yoshitaka
Y
Terada
Yoshio
Y
D001798:Blood Proteins / Q000032:analysis / Q000235:genetics*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; D001798:Blood Proteins; D060749:alpha-2-HS-Glycoprotein; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose