Aberrant Hepatic TRIB3 Gene Expression in Insulin-resistant Obese Humans

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2010 May 13

PMID 20461355

Citations 32

Authors

H Oberkofler

A Pfeifenberger

S Soyal

T Felder

P Hahne

K Miller

F Krempler

W Patsch

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: 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/interpretation: 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.

Citing Articles

Delayed Gut Colonization Changes Future Insulin Resistance and Hepatic Gene Expression but Not Adiposity in Obese Mice.

Ebert M, Mentzel C, Brunse A, Krych L, Hansen C J Obes. 2024; 2024:5846674.

PMID: 39360185 PMC: 11446614. DOI: 10.1155/2024/5846674.

Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets.

Mastoridou E, Goussia A, Kanavaros P, Charchanti A Int J Mol Sci. 2023; 24(21).

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Integration of dietary nutrition and TRIB3 action into diabetes mellitus.

Lu G, Li J, Gao T, Liu Q, Chen O, Zhang X Nutr Rev. 2023; 82(3):361-373.

PMID: 37226405 PMC: 10859691. DOI: 10.1093/nutrit/nuad056.

Upregulation of Tribbles decreases body weight and increases sleep duration.

Popovic R, Yu Y, Leal N, Fedele G, Loh S, Martins L Dis Model Mech. 2023; 16(4).

PMID: 37083954 PMC: 10151826. DOI: 10.1242/dmm.049942.

TRAF6 Suppresses the Development of Pulmonary Fibrosis by Attenuating the Activation of Fibroblasts.

Min J, Li Q, Liu S, Wang Q, Yin M, Zhang Y Front Pharmacol. 2022; 13:911945.

PMID: 35668944 PMC: 9163739. DOI: 10.3389/fphar.2022.911945.

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