Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans.
OBJECTIVE
The pseudokinase tribbles homologue 3 (Drosophila) (TRIB3) negatively interferes with insulin-mediated phosphorylation and activation of v-akt murine thymoma viral oncogene homologue 1 (AKT1, also known as protein kinase B). Animal studies have shown that Trib3 expression was higher in the fasting state and in animal models of diabetes, promoting hyperglycaemia presumably by increasing glucose production in the liver. Less is known about the role of TRIB3 in insulin resistance in humans, although a gain-of-function mutation associated with abnormalities related to insulin resistance has been described in TRIB3.


METHODS
We determined hepatic mRNA expression of TRIB3 and selected genes encoding enzymes, transcription factors and coactivators involved in glucose homeostasis. We also determined biochemical variables of intermediary metabolism in obese patients with varying degrees of insulin resistance.


RESULTS
In our study population hepatic TRIB3 mRNA expression was associated with surrogate markers of insulin resistance. TRIB3 expression was significantly increased in a subgroup with high HOMA of insulin resistance (HOMA-IR) compared with a low HOMA-IR group (p = 0.0033). TRIB3 transcript levels were correlated with PEPCK (also known as PCK2) mRNA expression (p = 0.0014) and mRNA expression of PPARGC1A (p = 0.0020), PPARGC1B (p < 0.0001), USF1 (p = 0.0017), FOXO1 (p = 0.0003) and SREBP-1c (also known as SREBF1; p = 0.0360). Furthermore ligands of peroxisome proliferator-activated receptor alpha/retinoid X receptor and overexpression of its coactivator PPARGC1A as well as overexpression of SREBP-1c and its coactivator PPARGC1B increased TRIB3 promoter activity in HepG2 cells.


CONCLUSIONS
We have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver.
Oberkofler
H
H
Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Müllner Hauptstr. 48, Salzburg, Austria. h.oberkofler@salk.at
Pfeifenberger
A
A
Soyal
S
S
Felder
T
T
Hahne
P
P
Miller
K
K
Krempler
F
F
Patsch
W
W
D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D009765:Obesity / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D006360:Heat-Shock Proteins; D047493:PPAR alpha; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D051780:Sterol Regulatory Element Binding Protein 1; C474831:TRIB3 protein, human; D014157:Transcription Factors; D014212:Tretinoin; C006253:pirinixic acid; D017346:Protein Serine-Threonine Kinases
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