IRIG: HDAC in center stage of metabolic disorder
06/01/2011 21:50
Synthetic PPARg ligands (such as TZDs) have been the
most powerful insulin sensitizers in the treatment of
type 2 diabetes in clinics. In the two TZD-based
medicines (rosiglitazone and pioglitazone),
rosiglitazone was withdrawn in the European market
last year and will be removed from the pharmacy store
in US by this November (FDA news: ). The
rosiglitazone-associated heart failure is responsible
for the end of its market performance in Europe and
US. A potential side effect in bladder cancer is
another threat to the value of TZD-based medicines
for type 2 diabetes.
Does laboratory research provide any new lead to drug targets/candidates that may replace TZD-based medicines? In the current issue of Cell, a study suggests that histone deacetylases (HDACs) are new drug targets in liver for improvement of insulin sensitivity or glucose metabolism. The study shows that HDACs (3 4, 5 and 7) works together to enhance glucose production in hepatocytes by activation of FOXO1. This pathway leads to an increase in hepatic gluconeogenesis by expression of G6Pase. The study provides an outstanding alternative mechanism for the insulin sensitization activity of HDAC inhibitor (butyrate) in mice in our early report in Diabetes. Together, those studies suggest that HDACs may be a promising target for insulin sensitization. Additionally, there are many other new targets. In the current issue of Nature, two studies provide information about novel drug targets in liver for improvement of insulin sensitivity. Please find details in following papers:
1. Mihaylova, M.M., Vasquez, D.S., Ravnskjaer, K., Denechaud, P.D., Yu, R.T., Alvarez, J.G., Downes, M., Evans, R.M., Montminy, M., and Shaw, R.J: Class IIa Histone Deacetylases Are Hormone-Activated Regulators of FOXO and Mammalian Glucose Homeostasis. Cell 145: 607-621, 2011. (This paper is suggested by Kenneth J. Eilertsen at PBRC and the study is highlighted in Cell by a Preview at http://www.sciencedirect.com/science/article/pii/S0092867411004752).
2. Gao, Z., Yin, J., Zhang, J., Pope, C.R., E, W.R., Martin, R.J., Lefevre, M., Cefalu, W.T., and Ye, J: Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice. Diabetes 58: 1509-1517, 2009. (Link: http://diabetes.diabetesjournals.org/content/58/7/1509)
3. Fu, S., Yang, L., Li, P., Hofmann, O., Dicker, L., Hide, W., Lin, X., Watkins, S.M., Ivanov, A.R., and Hotamisligil, G.S: Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528-531, 2001. (link: http://links.ealert.nature.com/ctt?kn=48&ms=MzY2NTE0MzMS1&r=MjA1NjA0Nzg4 MgS2&b=2&j=MTAyMzczODY2S0&mt=1&rt=0)
4. Lee, J.M., Lee, Y.K., Mamrosh, J.L., Busby, S.A., Griffin, P.R., Pathak, M.C., Ortlund, E.A., and Moore, D.D: A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature advance online publication. 2011. (Link: http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature10111.html# supplementary-information)
Jim
-----------------------------------------------------------------
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm
Does laboratory research provide any new lead to drug targets/candidates that may replace TZD-based medicines? In the current issue of Cell, a study suggests that histone deacetylases (HDACs) are new drug targets in liver for improvement of insulin sensitivity or glucose metabolism. The study shows that HDACs (3 4, 5 and 7) works together to enhance glucose production in hepatocytes by activation of FOXO1. This pathway leads to an increase in hepatic gluconeogenesis by expression of G6Pase. The study provides an outstanding alternative mechanism for the insulin sensitization activity of HDAC inhibitor (butyrate) in mice in our early report in Diabetes. Together, those studies suggest that HDACs may be a promising target for insulin sensitization. Additionally, there are many other new targets. In the current issue of Nature, two studies provide information about novel drug targets in liver for improvement of insulin sensitivity. Please find details in following papers:
1. Mihaylova, M.M., Vasquez, D.S., Ravnskjaer, K., Denechaud, P.D., Yu, R.T., Alvarez, J.G., Downes, M., Evans, R.M., Montminy, M., and Shaw, R.J: Class IIa Histone Deacetylases Are Hormone-Activated Regulators of FOXO and Mammalian Glucose Homeostasis. Cell 145: 607-621, 2011. (This paper is suggested by Kenneth J. Eilertsen at PBRC and the study is highlighted in Cell by a Preview at http://www.sciencedirect.com/science/article/pii/S0092867411004752).
2. Gao, Z., Yin, J., Zhang, J., Pope, C.R., E, W.R., Martin, R.J., Lefevre, M., Cefalu, W.T., and Ye, J: Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice. Diabetes 58: 1509-1517, 2009. (Link: http://diabetes.diabetesjournals.org/content/58/7/1509)
3. Fu, S., Yang, L., Li, P., Hofmann, O., Dicker, L., Hide, W., Lin, X., Watkins, S.M., Ivanov, A.R., and Hotamisligil, G.S: Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528-531, 2001. (link: http://links.ealert.nature.com/ctt?kn=48&ms=MzY2NTE0MzMS1&r=MjA1NjA0Nzg4 MgS2&b=2&j=MTAyMzczODY2S0&mt=1&rt=0)
4. Lee, J.M., Lee, Y.K., Mamrosh, J.L., Busby, S.A., Griffin, P.R., Pathak, M.C., Ortlund, E.A., and Moore, D.D: A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature advance online publication. 2011. (Link: http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature10111.html# supplementary-information)
Jim
-----------------------------------------------------------------
Jianping Ye, MD
Professor of Molecular Biology
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road
Baton Rouge, LA 70808
Phone: (225)763-3163
E-mail: yej@pbrc.edu
Webpage: http://labs.pbrc.edu/generegulation/index.htm
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