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Ahmed Bettaieb’s Research History

Contributions to Science

Research activities of Ahmed Bettaieb, while pursuing his PhD, were focused on trying to uncover the molecular mechanism and cellular signaling pathways in cancer cells in response to noninvasive biological methods, such as hyperthermia. Under the direction of Diana Averill-Bates, his findings were essential in uncovering ER stress as a potential molecular mechanism through which hyperthermia can cause cancer cells death. In this regard, hyperthermia could be useful in cancer therapy through regulating ER stress pathways in tumor cells.

  1. Bettaieb A and Averill-Bates DA (2005) Thermotolerance induced at a mild temperature of 40 degrees C protects cells against heat shock-induced apoptosis. J Cell Physiol 205(1): 47-57.

  2. Bettaieb A and Averill-Bates DA (2008) Thermotolerance induced at a fever temperature of 40 degrees C protects cells against hyperthermia-induced apoptosis mediated by death receptor signalling. Biochem Cell Biol 86(6): 521-538.

  3. Bettaieb A and Averill-Bates DA (2015) Thermotolerance induced at a mild temperature of 40 degrees C alleviates heat shock-induced ER stress and apoptosis in HeLa cells. Biochimica et biophysica acta 1853(1): 52-62.

  4. Glory A, Bettaieb A and Averill-Bates DA (2014) Mild thermotolerance induced at 40 degrees C protects cells against hyperthermia-induced pro-apoptotic changes in Bcl-2 family proteins. International journal of hyperthermia: the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 30(7): 502-512.

During his tenure at at University of California-Davis, he achieved several breakthroughs that enhanced our understanding of metabolic regulation. Under the supervision of Fawaz Haj, Ahmed Bettaieb’s research activities were focused on addressing the metabolic and non-metabolic functions of protein tyrosine phosphatases, namely PTP1B, TCPTP and SHP2. Using combined genetic, biochemical, molecular, and mass spectroscopy approaches, he identified new physiological substrates for PTP1B in the adipose and pancreas tissues and provided new mechanistic and functional insights into the role of PTP1B in obesity, Type 2 diabetes, and acute pancreatitis. Similarly, he addressed the physiological role of hepatic Shp2 using liver-specific deletion and demonstrated that liver-specific Shp2 deficient mice gained less weight and exhibited increased energy expenditure compared with controls. In addition, hepatic Shp2 deficiency led to decreased liver steatosis and prevented the development of insulin resistance following high fat feeding. These studies identified hepatic Shp2 as a novel regulator of systemic energy balance. Furthermore, he investigated the endocrine and exocrine functions of TCPTP using pancreas-specific deletion and demonstrated that pancreatic TCPTP deficiency mitigated acute pancreatitis in mice and affected pancreatic beta cell function and insulin secretion.

  1. Matsuo, K., et al., Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. J Biol Chem, 2010. 285(51): p. 39750-8.

  2. Nagata, N., et al., Hepatic Src homology phosphatase 2 regulates energy balance in mice. Endocrinology, 2012. 153(7): p. 3158-69.

  3. Bettaieb, A., et al., Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein-induced acute pancreatitis. Cell Commun Signal, 2014. 12: p. 13.

  4. Xi, Y.L., S. ; Bettaieb, A.; K. Matsuo; I Matsuo; E. Hosein; S. Chahed; F. Wiede; S. Zhang; Z.Y. Zhang; R. N. Kulkarni; T. Tiganis; F. G. Haj. , Pancreatic T cell protein-tyrosine phosphatase deficiency affects beta cell function. Diabetologia, 2014.

In collaboration with Bruce Hammock (University of California Davis), Bettaieb led several projects studying the metabolic and non-metabolic functions of soluble epoxide hydrolase (sEH). Using genetic, pharmacological, biochemical, and metabolomics approaches he demonstrated that sEH deficiency and pharmacological inhibition improves glucose tolerance, reduces pain-related behaviour, regulates endoplasmic reticulum stress and fibrosis, and attenuates acute pancreatitis. These studies provided new insights into sEH metabolic functions and the molecular mechanisms mediating its actions. Importantly, attenuation of pain by sEH pharmacological inhibition is being tested for human therapeutic intervention and initial results are promising

  1. Bettaieb, A., Chahed, S., Bachaalany, S., et al. (2015). Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice. Molecular pharmacology.

  2. Bettaieb, A., Chahed, S., Tabet, G., et al. (2014). Effects of soluble epoxide hydrolase deficiency on acute pancreatitis in mice. PloS one 9, e113019.

  3. Bettaieb, A., Nagata, N., AbouBechara, D., et al. (2013). Soluble epoxide hydrolase deficiency or inhibition attenuates diet-induced endoplasmic reticulum stress in liver and adipose tissue. The Journal of biological chemistry 288, 14189-14199.

  4. Inceoglu, B., Bettaieb, A., Trindade da Silva, C.A., et al. (2015). Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain. Proceedings of the National Academy of Sciences of the United States of America 112, 9082-9087.

  5. Inceoglu, B., Wagner, K.M., Yang, J., et al. (2012). Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes. Proceedings of the National Academy of Sciences of the United States of America 109, 11390-11395.

Diet can play a significant role in preventing the metabolic syndrome and its associated pathologies. In collaboration with P. Oteiza (University of California Davis), he investigated the effects of flavan-3-ol (−)-epicatechin (EC), the most abundant flavonoid in the human diet, on metabolic regulation. Together with Eleonora Cremonini and Marcela Vazquez Prieto, he demonstrated that EC prevented TNFa-induced activation of signaling cascades that led to inflammation and insulin resistance in adipocytes. They also found that EC supplementation to the diet mitigated high fructose-induced insulin resistance in rodents by modulating redox signaling and ER stress response in adipose and liver tissues.

  1. Bettaieb, A., Cremonini, E., Kang, H., et al. (2016). Anti-inflammatory actions of (-)-epicatechin in the adipose tissue of obese mice. The international journal of biochemistry & cell biology.

  2. Cremonini, E., Bettaieb, A., Haj, F.G., et al. (2016). (-)-Epicatechin improves insulin sensitivity in high fat diet-fed mice. Archives of biochemistry and biophysics 599, 13-21.

  3. Vazquez-Prieto, M.A., Bettaieb, A., Haj, F.G., et al. (2012). (-)-Epicatechin prevents TNFalpha-induced activation of signaling cascades involved in inflammation and insulin sensitivity in 3T3-L1 adipocytes. Archives of biochemistry and biophysics 527, 113-118.

  4. Vazquez Prieto, M.A., Bettaieb, A., Rodriguez Lanzi, C., et al. (2015). Catechin and quercetin attenuate adipose inflammation in fructose-fed rats and 3T3-L1 adipocytes. Molecular nutrition & food research 59, 622-633.