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.
Highlights
Beta-cell dysfunction is the hallmark of type 2 diabetes [1]
Palmitate stimulation of apoptosis was inversely related to its effect on Thioredoxin-interacting protein (TXNIP) expression, which was decreased by palmitate in a concentration-related manner (Figure 1B, C)
Normalization of TXNIP protein level to that at 22.2 mmol/l glucose showed that oleate inhibition of TXNIP at high glucose was significant and similar to that induced by palmitate (Figure 2B)
Summary
Little is known about the mechanisms that initiate type 2 diabetes; hyperglycemia and elevated free fatty acids (FFA) play an important role in the progression of beta-cell dysfunction in diabetes, a process called glucolipotoxicity [2]. Hyperglycemia and FFA act in concert to amplify the stress response in beta-cells, resulting in beta-cell dysfunction and apoptosis. Glucose and FFA differ in their regulation of the various stress pathways. Glucose-induced beta-cell apoptosis results mainly from oxidative stress with stimulation of the intrinsic mitochondrial death pathway, whereas ER stress plays a central role in FFAinduced beta-cell apoptosis [3,5]. The divergent effects of glucose and FFA on oxidative stress could result from differential regulation of the thioredoxin system [6]
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