Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein.
Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein.
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DOI：
10.1016/j.cmet.2009.10.007
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发表时间：
2009-12
期刊：
影响因子：
29
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Erion DM;Ignatova ID;Yonemitsu S;Nagai Y;Chatterjee P;Weismann D;Hsiao JJ;Zhang D;Iwasaki T;Stark R;Flannery C;Kahn M;Carmean CM;Yu XX;Murray SF;Bhanot S;Monia BP;Cline GW;Samuel VT;Shulman GI
在控制不佳的2型糖尿病（T2 DM）患者中，肝脏胰岛素抵抗和胰岛素生成增加导致空腹和餐后高血糖。由于CREB是促血管生成基因表达的关键调节因子，我们假设降低肝脏CREB表达可降低T2 DM啮齿动物模型的空腹高血糖。为了验证这一假设，我们使用CREB特异性反义寡核苷酸（阿索）敲低CREB在肝脏中的表达。CREB阿索治疗显著降低了ZDF大鼠、ob/ob小鼠和STZ治疗的高脂肪喂养的T2 DM大鼠模型中的空腹血糖浓度。令人惊讶的是，CREB阿索治疗还降低了血浆胆固醇和甘油三酯浓度，以及由于肝脏脂肪生成减少而导致的肝脏甘油三酯含量。这些结果表明，CREB是一个有吸引力的治疗靶点，用于通过下调脂肪生成和脂肪生成基因表达来纠正与NAFLD和T2 DM相关的肝脏胰岛素抵抗和血脂异常。
In patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contributes to fasting and postprandial hyperglycemia. Since 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 a 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 NAFLD and T2DM by down regulation of both lipogenic and gluconeogenic gene expression.
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影响因子：
5.8
作者：
REAVEN, GM;CHEN, YDI;JASPAN, JB
通讯作者：
JASPAN, JB
影响因子：
29
作者：
Qi L;Saberi M;Zmuda E;Wang Y;Altarejos J;Zhang X;Dentin R;Hedrick S;Bandyopadhyay G;Hai T;Olefsky J;Montminy M
通讯作者：
Montminy M
影响因子：
64.8
作者：
Herzig, S;Hedrick, S;Montminy, M
通讯作者：
Montminy, M
影响因子：
7.7
作者：
Sorensen, Heidi;Brand, Christian L.;Shulman, Gerald I.
通讯作者：
Shulman, Gerald I.
影响因子：
4.8
作者：
Schroeder-Gloeckler, Jill M.;Rahman, Shaikh Mizanoor;Friedman, Jacob E.
通讯作者：
Friedman, Jacob E.