AMP-Activated Protein Kinase (AMPK) Mediates Nutrient Regulation of Thioredoxin-Interacting Protein (TXNIP) in Pancreatic Beta-Cells

Abstract

Thioredoxin-interacting protein (TXNIP) regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids) effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP). Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment of diabetes.

Metformin Temporal and Localized Effects on Gut Glucose Metabolism Assessed Using 18F-FDG PET in Mice

“…The former increases its levels through the binding of 2 glycolytic intermediates (glyceraldehyde-3-phosphate and glucose-6-phosphate) to the gene activators carbohydrate-response elements and Mondo (24). The latter exerts the opposite effect and inhibits TXNIP production in response to changes in metabolite availability (11) and the presence of metformin (25).…”

“…Finally, to verify the underlying molecular mechanisms, we assessed the prevalence of the phosphorylated form of a AMPK subunit, phosphorylated adenosine monophosphate (AMP)-activated protein kinase (pAMPK), as a primary sensor of energetic cell asset (10). Moreover, we completed this analysis with the measurement of messenger RNA levels encoding for thioredoxin-interacting protein (TXNIP), a gene whose expression is powerfully suppressed by pAMPK yet stimulated by glucose (11).…”

Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways

“…However, unlike glucose, elevated free fatty acids do not increase ␤-cell TXNIP expression, and TXNIP deficiency does not effectively protect against fatty acid-induced ␤-cell death (6,10). This suggests that different ␤-cell stressors have distinct effects on TXNIP expression and raises the question of how cytokines might affect ␤-cell TXNIP.…”

Thioredoxin-Interacting Protein Stimulates Its Own Expression via a Positive Feedback Loop

“…The phosphorylation status of ChREBP has been shown to be mainly regulated by protein phosphatase 2A (PP2A) (27) and by AMPK (28,29). We therefore first used the protein serine/threonine phosphatase inhibitor okadaic acid and indeed found that it was able to counteract the TX-NIP-induced expression of endogenous TXNIP as well as of L-PK (Supplemental Figure 5, A and B) raising the possibility that activation of PP2A was involved in the observed TXNIP effects.…”