Type II Diabetes Mellitus (T2DM) is a metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. Over 170 million people worldwide suffer from T2DM and the prevalence of this disease is steadily rising; indicating that new insights into the molecular mechanisms underlying this disease are sorely needed. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich elements in the 3'-untranslated region (3'-UTR) of target mRNA molecules, and promotes their degradation. Several lines of evidence have suggested a link between TTP and metabolic processes. First, TTP is an insulin-responsive gene and its reduced expression has been linked to metabolic syndrome and insulin-resistance in humans. Second, deletion of the yeast homolog of TTP, Cth1/2p, has been shown to increase mitochondrial proteins involved in oxidative metabolism. Lastly, our recent results show that TTP mRNA and protein levels are reduced in livers of diabetic mice, and that liver-specific deletion of TTP increases systemic glucose sensitivity in a mouse model of obesity-induced diabetes. We have also identified two targets of TTP involved in glucose oxidation whose expression increases in TTP knock-out primary hepatocytes; Pyruvate Dehydrogenase - E2 subunit (PDC-E2), which converts pyruvate into acetyl-CoA for subsequent use in the TCA cycle, and Lipoic Acid Synthase (LIAS), the rate limiting enzyme in the synthesis of lipoic acid (LA). Coordinated regulation of LIAS and PDC-E2 is crucial as LA is a required cofactor for PDC-E2 function. My central hypothesis is that insulin stimulated expression of TTP reduces hepatic glucose utilization by modulating the levels of PDC-E2 and LIAS and that loss of TTP in the liver protects against the development of DM through its effects on the levels of these proteins and glucose metabolism. I will test this hypothesis in two specific aims.
In Aim 1, I will determine whether TTP regulates hepatic glucose metabolism through a PDC-dependent pathway and through its role in the biosynthesis of LA.
In Aim 2, I will determine whether a reduction in hepatic TTP expression is protective against the development of diabetes due to its effects on hepatic glucose utilization. These lines of investigation are the first to look at the role of an mRNA binding protein that causes mRNA degradation in the regulation of liver metabolism and promise to advance our knowledge of the role of TTP in regulating cellular metabolism. These studies may potentially lead to the development of novel therapies for disorders of glucose metabolism, such as DM.
Recently, we discovered a novel role for a protein called tristetraprolin (TTP) in managing glucose metabolism in the liver. This proposal seeks to determine the mechanism by which TTP can regulate liver cell metabolism under normal conditions and in diabetes. We hope to use this knowledge to expand the current approach to treating metabolic disorders, such as metabolic syndrome and type II diabetes mellitus, by establishing TTP as a therapeutic target capable of regulating glucose metabolism.
| Shapiro, Jason S; Chang, Hsiang-Chun; Ardehali, Hossein (2017) Iron and Sex Cross Paths in the Heart. J Am Heart Assoc 6: |
