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.
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Derek M
authors: DM
authors: Erion
authors: Irena D
authors: ID
authors: Ignatova
authors: Shin
authors: S
authors: Yonemitsu
authors: Yoshio
authors: Y
authors: Nagai
authors: Paula
authors: P
authors: Chatterjee
authors: Dirk
authors: D
authors: Weismann
authors: Jennifer J
authors: JJ
authors: Hsiao
authors: Dongyan
authors: D
authors: Zhang
authors: Takanori
authors: T
authors: Iwasaki
authors: Romana
authors: R
authors: Stark
authors: Clare
authors: C
authors: Flannery
authors: Mario
authors: M
authors: Kahn
authors: Christopher M
authors: CM
authors: Carmean
authors: Xing Xian
authors: XX
authors: Yu
authors: Susan F
authors: SF
authors: Murray
authors: Sanjay
authors: S
authors: Bhanot
authors: Brett P
authors: BP
authors: Monia
authors: Gary W
authors: GW
authors: Cline
authors: Varman T
authors: VT
authors: Samuel
authors: Gerald I
authors: GI
authors: Shulman
mesh_terms: 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*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; D002784:Cholesterol; D005947:Glucose