Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of CAMP Response Element-binding Protein

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2009 Dec 1

PMID 19945407

Citations 60

Authors

Derek M Erion

Irena D Ignatova

Shin Yonemitsu

Yoshio Nagai

Paula Chatterjee

Dirk Weismann

Jennifer J Hsiao

Dongyan Zhang

Takanori Iwasaki

Romana Stark

Clare Flannery

Mario Kahn

Christopher M Carmean

Xing Xian Yu

Susan F Murray

Sanjay Bhanot

Brett P Monia

Gary W Cline

Varman T Samuel

Gerald I Shulman

Affiliations

Soon will be listed here.

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.

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