Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein.
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.
Erion
Derek M
DM
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Ignatova
Irena D
ID
Yonemitsu
Shin
S
Nagai
Yoshio
Y
Chatterjee
Paula
P
Weismann
Dirk
D
Hsiao
Jennifer J
JJ
Zhang
Dongyan
D
Iwasaki
Takanori
T
Stark
Romana
R
Flannery
Clare
C
Kahn
Mario
M
Carmean
Christopher M
CM
Yu
Xing Xian
XX
Murray
Susan F
SF
Bhanot
Sanjay
S
Monia
Brett P
BP
Cline
Gary W
GW
Samuel
Varman T
VT
Shulman
Gerald I
GI
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000628:therapy; D005234:Fatty Liver / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense; D051381:Rats; D014280:Triglycerides / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; D002784:Cholesterol; D005947:Glucose