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 -