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Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes
Umut Özcan,
Erkan Yilmaz,
Lale Özcan,
Masato Furuhashi,
Eric Vaillancourt,
Ross O. Smith,
Cem Z. Görgün,
Gökhan S. Hotamisligil*
Abstract:
Endoplasmic reticulum (ER) stress is a key link between obesity,insulin resistance, and type 2 diabetes. Here, we provide evidencethat this mechanistic link can be exploited for therapeuticpurposes with orally active chemical chaperones. 4-Phenyl butyricacid and taurine-conjugated ursodeoxycholic acid alleviatedER stress in cells and whole animals. Treatment of obese anddiabetic mice with these compounds resulted in normalizationof hyperglycemia, restoration of systemic insulin sensitivity,resolution of fatty liver disease, and enhancement of insulinaction in liver, muscle, and adipose tissues. Our results demonstratethat chemical chaperones enhance the adaptive capacity of theER and act as potent antidiabetic modalities with potentialapplication in the treatment of type 2 diabetes.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
* To whom correspondence should be addressed. E-mail: ghotamis{at}hsph.harvard.edu
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Hepatic Nuclear Factor 1{alpha} (HNF1{alpha}) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes {beta}-Cells to Endoplasmic Reticulum Stress.
C. L. Kirkpatrick, A. Wiederkehr, M. Baquie, D. Akhmedov, H. Wang, B. R. Gauthier, I. Akerman, H. Ishihara, J. Ferrer, and C. B. Wollheim (2011)
J. Biol. Chem.
286, 32300-32312
|Abstract »|Full Text »|PDF »
Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways.
T. Promlek, Y. Ishiwata-Kimata, M. Shido, M. Sakuramoto, K. Kohno, and Y. Kimata (2011)
Mol. Biol. Cell
22, 3520-3532
|Abstract »|Full Text »|PDF »
Different fatty acids inhibit apoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy.
J. M. Caviglia, C. Gayet, T. Ota, A. Hernandez-Ono, D. M. Conlon, H. Jiang, E. A. Fisher, and H. N. Ginsberg (2011)
J. Lipid Res.
52, 1636-1651
|Abstract »|Full Text »|PDF »
Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats.
B. P. Cummings, A. Bettaieb, J. L. Graham, K. L. Stanhope, R. Dill, G. J. Morton, F. G. Haj, and P. J. Havel (2011)
PNAS
108, 14670-14675
|Abstract »|Full Text »|PDF »
Sirtuin 1 (SIRT1) Protein Degradation in Response to Persistent c-Jun N-terminal Kinase 1 (JNK1) Activation Contributes to Hepatic Steatosis in Obesity.
Z. Gao, J. Zhang, I. Kheterpal, N. Kennedy, R. J. Davis, and J. Ye (2011)
J. Biol. Chem.
286, 22227-22234
|Abstract »|Full Text »|PDF »
Haploid Insufficiency of Suppressor Enhancer Lin12 1-like (SEL1L) Protein Predisposes Mice to High Fat Diet-induced Hyperglycemia.
A. B. Francisco, R. Singh, H. Sha, X. Yan, L. Qi, X. Lei, and Q. Long (2011)
J. Biol. Chem.
286, 22275-22282
|Abstract »|Full Text »|PDF »
Peptidyl-prolyl Cis/Trans Isomerase NIMA-interacting 1 Associates with Insulin Receptor Substrate-1 and Enhances Insulin Actions and Adipogenesis.
Y. Nakatsu, H. Sakoda, A. Kushiyama, J. Zhang, H. Ono, M. Fujishiro, T. Kikuchi, T. Fukushima, M. Yoneda, H. Ohno, et al. (2011)
J. Biol. Chem.
286, 20812-20822
|Abstract »|Full Text »|PDF »
Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle.
G. Peng, L. Li, Y. Liu, J. Pu, S. Zhang, J. Yu, J. Zhao, and P. Liu (2011)
Endocrinology
152, 2206-2218
|Abstract »|Full Text »|PDF »
Phosphatidylethanolamines Modified by {gamma}-Ketoaldehyde ({gamma}KA) Induce Endoplasmic Reticulum Stress and Endothelial Activation.
L. Guo, Z. Chen, B. E. Cox, V. Amarnath, R. F. Epand, R. M. Epand, and S. S. Davies (2011)
J. Biol. Chem.
286, 18170-18180
|Abstract »|Full Text »|PDF »
Lecithin Cholesterol Acyltransferase Null Mice Are Protected from Diet-induced Obesity and Insulin Resistance in a Gender-specific Manner through Multiple Pathways.
L. Li, M. A. Hossain, S. Sadat, L. Hager, L. Liu, L. Tam, S. Schroer, L. Huogen, I. G. Fantus, P. W. Connelly, et al. (2011)
J. Biol. Chem.
286, 17809-17820
|Abstract »|Full Text »|PDF »
Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver.
Y. Li, S. Xu, A. Giles, K. Nakamura, J. W. Lee, X. Hou, G. Donmez, J. Li, Z. Luo, K. Walsh, et al. (2011)
FASEB J
25, 1664-1679
|Abstract »|Full Text »|PDF »
Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys.
K. Kavanagh, D. M. Flynn, K. A. Jenkins, L. Zhang, and J. D. Wagner (2011)
Am J Physiol Endocrinol Metab
300, E894-E901
|Abstract »|Full Text »|PDF »
