CARD3 Deficiency Exacerbates Diet-Induced Obesity, Hepatosteatosis, and Insulin Resistance in Male Mice
CARD3 Deficiency Exacerbates Diet-Induced Obesity, Hepatosteatosis, and Insulin Resistance in Male Mice
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CARD3 缺陷会加剧雄性小鼠饮食引起的肥胖、肝脂肪变性和胰岛素抵抗
DOI：
10.1210/en.2012-1911
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发表时间：
2013-02-01
期刊：
影响因子：
4.8
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Wang, Xin-An;Deng, Shan;Li, Hongliang
半胱天冬酶激活和募集结构域3（CARD 3）是具有N-末端丝氨酸/苏氨酸激酶结构域和C-末端CARD的61-kDa蛋白激酶。以前对CARD 3功能的研究主要集中在其在免疫反应和炎症性疾病中的作用。肥胖是一个世界性的健康问题，通常被认为是一种炎症性疾病。出乎意料的是，我们发现肥胖期间CARD 3表达较低。在这项研究中，我们使用CARD 3基因敲除（KO）和野生型（WT）小鼠喂养高脂饮食（HFD）24周，探索肥胖的生物学和遗传基础。我们证明KO小鼠比WT同窝出生的小鼠更肥胖，并且KO小鼠在HFD喂养24周后表现出明显的内脏脂肪积累和肝脏重量增加。与WT对照组相比，我们还观察到KO小鼠中更严重的脂肪肝。HFD喂养的KO小鼠的肝脏脂肪变性与关键脂肪生成酶和胆固醇合成酶的表达显著增加有关，而参与β-氧化的酶的表达显著降低。此外，我们证实了抑制AMP激活的蛋白激酶信号和激活内质网应激反应。脂肪肝损害了全身糖脂代谢，进一步加重了胰岛素抵抗，并通过M1/M2（促炎症和抗炎）型转换和核因子-κ B通路的激活抑制Akt信号和上调全身炎症。我们的研究证明了CARD 3在代谢中的关键作用，并表明CARD 3缺乏促进了2型糖尿病的饮食诱导表型。（内分泌学154：685-697，2013）
Caspase activation and recruitment domain 3 (CARD3) is a 61-kDa protein kinase with an N-terminal serine/threonine kinase domain and a C-terminal CARD. Previous research on the function of CARD3 has focused on its role in the immune response and inflammatory diseases. Obesity is now a worldwide health problem and is generally recognized as an inflammatory disease. Unexpectedly, we found that CARD3 expression was lower during obesity. In this study, we explored the biological and genetic bases of obesity using CARD3-knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD) for 24 weeks. We demonstrate that KO mice were more obese than their WT littermates, and KO mice exhibited obvious visceral fat accumulation and liver weight gains after 24 weeks of HFD feeding. We also observed more severe hepatosteatosis in KO mice compared with the WT controls. Hepatic steatosis in the HFD-fed KO mice was linked to a significant increase in the expression of key lipogenic and cholesterol synthesis enzymes, whereas the expression of the enzymes involves in beta-oxidation was dramatically reduced. Furthermore, we confirmed the repression of AMP-activated protein kinase signaling and activation of the endoplasmic reticulum stress response. Fatty liver impaired the global glucose and lipid metabolism, which further exacerbated the insulin resistance associated with the repression of Akt signaling and up-regulated systemic inflammation through the M1/M2 (pro-and anti-inflammation) type switch and the activation of the nuclear factor-kappa B pathway. Our studies demonstrate the crucial role of CARD3 in metabolism and indicate that CARD3 deficiency promotes the diet-induced phenotype of type 2 diabetes. (Endocrinology 154: 685-697, 2013)