Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein

Derek M Erion; Irena Ignatova-Todorova; Shin Yonemitsu; Yoshio Nagai; Paula Chatterjee; Dirk Weismann; Jennifer J Hsiao; Dongyan Zhang; Takanori Iwasaki; Romana Stark; Clare A Flannery; Mario Khan; Christopher M Carmean; Xingxian Yu; Susan F Murray; Sanjay Bhanot; Brett P Monia; Gary Cline; Varman T Samuel; Gerald I Shulman

doi:10.1016/j.cmet.2009.10.007

Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein

Derek M Erion, Irena Ignatova-Todorova, Shin Yonemitsu, Yoshio Nagai, Paula Chatterjee, Dirk Weismann, Jennifer J Hsiao, Dongyan Zhang, Takanori Iwasaki, Romana Stark, Clare A Flannery, Mario Khan, Christopher M Carmean, Xingxian Yu, Susan F Murray, Sanjay Bhanot, Brett P Monia, Gary Cline, Varman T Samuel, Gerald I Shulman

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

In patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.

Original language	English
Pages (from-to)	499 - 506
Number of pages	8
Journal	Cell Metabolism
Volume	10
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2009.10.007
Publication status	Published - 2009
Externally published	Yes

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Erion, D. M., Ignatova-Todorova, I., Yonemitsu, S., Nagai, Y., Chatterjee, P., Weismann, D., Hsiao, J. J., Zhang, D., Iwasaki, T., Stark, R., Flannery, C. A., Khan, M., Carmean, C. M., Yu, X., Murray, S. F., Bhanot, S., Monia, B. P., Cline, G., Samuel, V. T., & Shulman, G. I. (2009). Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein. Cell Metabolism, 10(6), 499 - 506. https://doi.org/10.1016/j.cmet.2009.10.007

@article{17b8acb812944e21a526720d38cb6f6d,

title = "Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein",

abstract = "In patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.",

author = "Erion, {Derek M} and Irena Ignatova-Todorova and Shin Yonemitsu and Yoshio Nagai and Paula Chatterjee and Dirk Weismann and Hsiao, {Jennifer J} and Dongyan Zhang and Takanori Iwasaki and Romana Stark and Flannery, {Clare A} and Mario Khan and Carmean, {Christopher M} and Xingxian Yu and Murray, {Susan F} and Sanjay Bhanot and Monia, {Brett P} and Gary Cline and Samuel, {Varman T} and Shulman, {Gerald I}",

year = "2009",

doi = "10.1016/j.cmet.2009.10.007",

language = "English",

volume = "10",

pages = "499 -- 506",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Elsevier",

number = "6",

}

Erion, DM, Ignatova-Todorova, I, Yonemitsu, S, Nagai, Y, Chatterjee, P, Weismann, D, Hsiao, JJ, Zhang, D, Iwasaki, T, Stark, R, Flannery, CA, Khan, M, Carmean, CM, Yu, X, Murray, SF, Bhanot, S, Monia, BP, Cline, G, Samuel, VT & Shulman, GI 2009, 'Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein', Cell Metabolism, vol. 10, no. 6, pp. 499 - 506. https://doi.org/10.1016/j.cmet.2009.10.007

TY - JOUR

T1 - Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein

AU - Erion, Derek M

AU - Ignatova-Todorova, Irena

AU - Yonemitsu, Shin

AU - Nagai, Yoshio

AU - Chatterjee, Paula

AU - Weismann, Dirk

AU - Hsiao, Jennifer J

AU - Zhang, Dongyan

AU - Iwasaki, Takanori

AU - Stark, Romana

AU - Flannery, Clare A

AU - Khan, Mario

AU - Carmean, Christopher M

AU - Yu, Xingxian

AU - Murray, Susan F

AU - Bhanot, Sanjay

AU - Monia, Brett P

AU - Cline, Gary

AU - Samuel, Varman T

AU - Shulman, Gerald I

PY - 2009

Y1 - 2009

N2 - In patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.

AB - In patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.

UR - http://www.sciencedirect.com/science/article/pii/S1550413109003064#

U2 - 10.1016/j.cmet.2009.10.007

DO - 10.1016/j.cmet.2009.10.007

M3 - Article

VL - 10

SP - 499

EP - 506

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 6

ER -

Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein

Abstract

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