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 t...

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Vydáno v:Cell metabolism Ročník 10; číslo 6; s. 499
Hlavní autoři: Erion, Derek M, Ignatova, Irena D, Yonemitsu, Shin, Nagai, Yoshio, Chatterjee, Paula, Weismann, Dirk, Hsiao, Jennifer J, Zhang, Dongyan, Iwasaki, Takanori, Stark, Romana, Flannery, Clare, Kahn, Mario, Carmean, Christopher M, Yu, Xing Xian, Murray, Susan F, Bhanot, Sanjay, Monia, Brett P, Cline, Gary W, Samuel, Varman T, Shulman, Gerald I
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.12.2009
Témata:
Animals
Cholesterol - metabolism
Cyclic AMP Response Element-Binding Protein - antagonists & inhibitors
Cyclic AMP Response Element-Binding Protein - genetics
Cyclic AMP Response Element-Binding Protein - metabolism
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - physiopathology
Diabetes Mellitus, Type 2 - therapy
Disease Models, Animal
Dyslipidemias - therapy
Fatty Liver - genetics
Fatty Liver - physiopathology
Fatty Liver - therapy
Glucose - metabolism
Insulin Resistance - genetics
Lipogenesis - physiology
Liver - metabolism
Liver - physiopathology
Male
Mice
Oligonucleotides, Antisense
Rats
Triglycerides - metabolism
ISSN:1932-7420, 1932-7420
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2009.10.007