IRIG: AMPK, HIF-1b and APPL1 in Cell Metabolism
05/15/2009 09:37
Here are three
outstanding papers in the current issue of Cell
Metabolism. Click the title.
Review
AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome
B.B. Zhang, G. Zhou, and C. Li
Articles
APPL1 Potentiates Insulin‑Mediated Inhibition of Hepatic Glucose Production and Alleviates Diabetes via Akt Activation in Mice
K.K.Y. Cheng, M.A. Iglesias, K.S.L. Lam, Y. Wang, G. Sweeney, W. Zhu, P.M. Vanhoutte, E.W. Kraegen, and A. Xu
Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. This study provides evidence demonstrating that the endosomal adaptor protein APPL1 alleviates hepatic insulin resistance by potentiating insulin‑mediated suppression of glucose production in obese mice. In hepatocytes, APPL1 interacts with the protein kinase Akt and blocks the interaction of Akt with its endogenous inhibitor Tribble3, thereby facilitating Akt activation by promoting its translocation to the plasma membrane and endosomes. These findings suggest that APPL1 and Tribble3 act as a "Yin and Yang" pair that tightly controls hepatic glucose production by fine‑tuning the insulin‑evoked Akt signaling cascade.
Ablation of ARNT/HIF1β in Liver Alters Gluconeogenesis, Lipogenic Gene Expression, and Serum Ketones
X.L. Wang, R. Suzuki, K. Lee, T. Tran, J.E. Gunton, A.K. Saha, M.‑E. Patti, A. Goldfine, N.B. Ruderman, F.J. Gonzalez, and C.R. Kahn
Diabetic patients have reduced levels of the transcription factor ARNT/HIF1β in the pancreas, a reduction which is associated with impaired insulin secretion. Here, we show that ARNT is also reduced in the liver of obese individuals with type 2 diabetes. We further demonstrate that liver‑specific knockout of ARNT/HIF1β in mice affects transcriptional networks resulting in increased gluconeogenesis and dyslipidemia but also hypoketonemia, independently of alterations in expression of enzymes in fatty acid β oxidation or hepatic ketogenesis. Our results suggest that modulation of ARNT could be a therapeutic approach in treating diabetes, fatty liver, and the metabolic syndrome.
By Jianping
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
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
Review
AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome
B.B. Zhang, G. Zhou, and C. Li
Articles
APPL1 Potentiates Insulin‑Mediated Inhibition of Hepatic Glucose Production and Alleviates Diabetes via Akt Activation in Mice
K.K.Y. Cheng, M.A. Iglesias, K.S.L. Lam, Y. Wang, G. Sweeney, W. Zhu, P.M. Vanhoutte, E.W. Kraegen, and A. Xu
Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. This study provides evidence demonstrating that the endosomal adaptor protein APPL1 alleviates hepatic insulin resistance by potentiating insulin‑mediated suppression of glucose production in obese mice. In hepatocytes, APPL1 interacts with the protein kinase Akt and blocks the interaction of Akt with its endogenous inhibitor Tribble3, thereby facilitating Akt activation by promoting its translocation to the plasma membrane and endosomes. These findings suggest that APPL1 and Tribble3 act as a "Yin and Yang" pair that tightly controls hepatic glucose production by fine‑tuning the insulin‑evoked Akt signaling cascade.
Ablation of ARNT/HIF1β in Liver Alters Gluconeogenesis, Lipogenic Gene Expression, and Serum Ketones
X.L. Wang, R. Suzuki, K. Lee, T. Tran, J.E. Gunton, A.K. Saha, M.‑E. Patti, A. Goldfine, N.B. Ruderman, F.J. Gonzalez, and C.R. Kahn
Diabetic patients have reduced levels of the transcription factor ARNT/HIF1β in the pancreas, a reduction which is associated with impaired insulin secretion. Here, we show that ARNT is also reduced in the liver of obese individuals with type 2 diabetes. We further demonstrate that liver‑specific knockout of ARNT/HIF1β in mice affects transcriptional networks resulting in increased gluconeogenesis and dyslipidemia but also hypoketonemia, independently of alterations in expression of enzymes in fatty acid β oxidation or hepatic ketogenesis. Our results suggest that modulation of ARNT could be a therapeutic approach in treating diabetes, fatty liver, and the metabolic syndrome.
By Jianping
‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑
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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