Cysteine thiol modifications, S-nitrosylation and protein farnesylation, in the pathogenesis of diabetes and stress/inflammation-induced metabolic reprogramming
The overall objectives of the research program are to clarify the roles of cysteine thiol modifications, S-nitrosylation and protein farnesylation, in the pathogenesis of obesity- and stress-induced insulin resistance and pancreatic beta-cell damage, and stress/inflammation-induced metabolic reprogramming.
Ongoing projects include:
- Inducible nitric oxide synthase (iNOS)-induced S-nitrosylation and obesity-induced insulin resistance: We have shown that: (a) iNOS inhibition significantly ameliorates whole-body insulin resistance, and improves depressed expression of insulin receptor substrate (IRS)-1 and IRS-2, and IRSs-mediated insulin signaling in skeletal muscle and liver of obese, diabetic (ob/ob) mice; (b) S-nitrosylation reversibly inactivates Akt/PKB (c) S-nitrosylated Akt/PKB is increased in insulin-sensitive tissues, including skeletal muscle, of diabetic (ob/ob) mice, as compared with wild-type control mice; and (d) liver-specific overexpression of iNOS is sufficient to induce hepatic insulin resistance and hyperglycemia in mice. The target molecules of S-nitrosylation in the liver of diabetic (db/db) mice and roles of iNOS and protein S-nitrosylation as an upstream enhancer of the sustained activation of inflammatory/stress signaling pathways in obesity-induced insulin resistance are under investigation.
- Role of S-nitrosoglutathione (GSNO) reductase (GSNOR) in pancreatic beta-cell dysfunction: We have shown that: (a) iNOS inhibitor ameliorates hyperglycemia with increased plasma insulin levels in diabetic (db/db) mice on BKS background; and (b) gene disruption of GSNOR confers increased susceptibility to streptozotocin-induced diabetes and proinflammatory cytokine- and NO donors-induced beta-cell death; and (c) iNOS decreases IRS-2 protein expression by enhancing proteasome-mediated degradation in a GSK-3β-dependent manner in pancreatic beta-cells. Investigation on the precise role of GSNOR is underway, using pancreatic beta-cell specific GSNOR overexpressing transgenic mice and GSNOR-/- iNOS-/- double knockout mice.
- Protein farnesylation and metabolic reprogramming: The precise mechanisms of the lipid-lowering-independent pleiotropic beneficial effects of statins are not fully understood. The research in this program indicates that inducible and reversible protein farnesylation occurs in response to stress/inflammation, which challenges the existing paradigm that protein farnesylation is constitutive and irreversible. Recent data showed that inhibition of inducible farnesylation reversed or ameliorated inflammation-induced insulin resistance and metabolic reprogramming (i.e., aerobic glycolysis) in cultured cells and skeletal muscle of burned mice. Currently, this research team is identifying novel target proteins for inducible and reversible farnesylation that play an important role in metabolic reprogramming.
1. Tanioka, T., Tamura, Y., Fukaya, M., Kim, M., Shimizu, N., Kaneki, M. iNOS and NO donor decrease IRS-2 protein expression by promoting proteasome-dependent degradation in pancreatic b-cells: Involvement of GSK-3b. J Biol Chem. 2011;286:29388-96. PMCID: PMC3190744
2. Sugita M, Sugita H, Kim M, Mao J, Yasuda Y, Habiro M, Yasuhara S, Shimizu N, Martyn JAJ, Kaneki M. iNOS deficiency ameliorates skeletal muscle insulin resistance but does not alter unexpected lower blood glucose levels after burn injury in C57BL/6 mice. Metabolism. 2012 Jan;61(1):127-36. PMCID: PMC3304504
3. Shinozaki, S., Choi, C-S., Shimizu, S., Yamada, M., Kim, M., Zhang, T., Dong, H., Kim, Y-B., Kaneki, M. Liver-specific iNOS expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice. J Biol Chem. 2011;286:34959-75. PMCID: PMC3186386
4. Tamura Y, Chiba Y, Tanioka T, Shimizu N, Shinozaki S, Yamada M, Kaneki K, Mori S, Araki A, Ito H, Kaneki M. NO donor induces Nec-1-inhibitable, but RIP1-independent, necrotic cell death in pancreatic β-cells. FEBS Lett. 2011;585:3058-64. PMCID: PMC3304503
5. Yasuda Y, Fukushima Y, Kaneki M, Martyn J. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats. Biochem Biophys Res Commun. 2013 Feb 1;431(1):81-5. PMCID: PMC3566703