Hepatocyte Toll-Like Receptor 4 Mediates Alcohol-Induced Insulin Resistance in Mice.
Hepatocyte Toll-Like Receptor 4 Mediates Alcohol-Induced Insulin Resistance in Mice.
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DOI：
10.3390/biom13030454
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发表时间：
2023-03-01
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
越来越多的证据表明，酒精过度消费和胰岛素抵抗的发展之间存在联系。然而，其潜在机制尚未完全了解。为了研究肝细胞Toll样受体4（TLR 4）在酒精诱导的胰岛素抵抗中的需求和充分性，我们使用了两种小鼠模型（Tlr 4fl/fl和Tlr 4LoxTB），其分别允许仅在肝细胞中消融TLR 4（Tlr 4LKO）和在TLR 4无效背景下恢复肝细胞中内源性TLR 4表达（Tlr 4LoxTB × Alb-Cre）。使用Lieber-DeCarli喂养模型诱导小鼠的葡萄糖耐受不良和胰岛素抵抗。通过葡萄糖耐量试验、胰岛素耐量试验和胰岛素信号转导试验检测全身和组织特异性胰岛素敏感性。我们发现，酒精喂养的肝细胞TLR 4缺陷小鼠（Tlr 4LKO）有较低的血糖水平响应于腹腔注射胰岛素。此外，在Tlr 4LKO小鼠的肝脏中观察到慢性酒精摄入后糖原合成酶激酶-3 β（GSK 3 β）的磷酸化增加。相反，当肝脏TLR 4在小鼠（Tlr 4LoxTB × Alb-Cre）中被重新激活时，与同窝对照（Tlr 4LoxTB）相比，酒精喂养导致这些小鼠的葡萄糖耐受不良。此外，酒精喂养的Tlr 4 LoxTB × Alb-Cre小鼠的肝脏和附睾白色脂肪组织（eWAT）中的AKT磷酸化显著降低，这与全身TLR 4再激活的小鼠（Tlr 4 LoxTB × Zp 3-Cre）相似。总的来说，这些研究结果表明，肝细胞TLR 4是必需的和足够的酒精过度消费诱导的胰岛素抵抗的发展。
Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4fl/fl and Tlr4LoxTB) that allow ablation of TLR4 only in hepatocytes (Tlr4LKO) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4LoxTB × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4LKO) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3β (GSK3β) was observed in the liver of Tlr4LKO mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4LoxTB × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4LoxTB). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4LoxTB × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4LoxTB × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.
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DOI：
10.1002/hep.22470
发表时间：
2008-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
通讯作者：
Szabo G
影响因子：
4.8
作者：
He, L;Simmen, FA;Badger, TM
通讯作者：
Badger, TM
影响因子：
3.4
作者：
Jia, Lin;Lee, Syann;Gautron, Laurent
通讯作者：
Gautron, Laurent
DOI：
10.1111/j.1530-0277.2011.01487.x
发表时间：
2011-08
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Inokuchi S;Tsukamoto H;Park E;Liu ZX;Brenner DA;Seki E
通讯作者：
Seki E
影响因子：
16.2
作者：
Bell, DSH
通讯作者：
Bell, DSH