The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner.
The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner.
复制标题
DOI：
10.1371/journal.pone.0204898
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Lybarger L
中科院分区：
文献类型：
--
作者：
Bhagwandin C;Ashbeck EL;Whalen M;Bandola-Simon J;Roche PA;Szajman A;Truong SM;Wertheim BC;Klimentidis YC;Ishido S;Renquist BJ;Lybarger L
2型糖尿病的典型特征是脂肪组织、骨骼肌和肝脏中的胰岛素抵抗，导致慢性高血糖症。此外，肥胖和2型糖尿病的特征在于慢性低度炎症。膜相关RING-CH-1（MARCH 1）是一种E3泛素连接酶，以抑制树突状细胞和B细胞的抗原呈递而闻名。最近发现MARCH 1通过泛素化负调节胰岛素受体的细胞表面水平。这反过来又损害了小鼠模型的胰岛素敏感性。在这里，我们报告说，MARCH 1缺陷（敲除; KO）的雌性小鼠表现出过度的体重增加和过度的内脏肥胖时，饲养标准的食物饮食，没有增加脂肪组织的炎症细胞浸润。相比之下，雄性MARCH 1 KO小鼠的体重增加和内脏肥胖与野生型（WT）雄性小鼠相似。两种性别的MARCH 1 KO小鼠的葡萄糖耐受性均高于WT小鼠。与雄性相比，雌性MARCH 1 KO小鼠的胰岛素应答组织（尤其是肝脏）中胰岛素受体水平通常较高，这可能部分解释了雄性和雌性MARCH 1 KO小鼠之间的差异。我们还通过在公开数据集中进行遗传关联测试，探索了MARCH 1在人类2型糖尿病风险中的潜在作用，并发现了提示关联的证据。总的来说，我们的数据表明免疫功能和糖尿病之间存在额外的联系，特别是MARCH 1作为脂质代谢和葡萄糖耐量的调节剂，其功能受到性别特异性因素的影响。
Type 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells. MARCH1 was recently found to negatively regulate the cell surface levels of the insulin receptor via ubiquitination. This, in turn, impaired insulin sensitivity in mouse models. Here, we report that MARCH1-deficient (knockout; KO) female mice exhibit excessive weight gain and excessive visceral adiposity when reared on standard chow diet, without increased inflammatory cell infiltration of adipose tissue. By contrast, male MARCH1 KO mice had similar weight gain and visceral adiposity to wildtype (WT) male mice. MARCH1 KO mice of both sexes were more glucose tolerant than WT mice. The levels of insulin receptor were generally higher in insulin-responsive tissues (especially the liver) from female MARCH1 KO mice compared to males, with the potential to account in part for the differences between male and female MARCH1 KO mice. We also explored a potential role for MARCH1 in human type 2 diabetes risk through genetic association testing in publicly-available datasets, and found evidence suggestive of association. Collectively, our data indicate an additional link between immune function and diabetes, specifically implicating MARCH1 as a regulator of lipid metabolism and glucose tolerance, whose function is modified by sex-specific factors.
登录
查看更多内容
影响因子：
16.6
作者：
Nagarajan, Arvindhan;Petersen, Max C.;Nasiri, Ali R.;Butrico, Gina;Fung, Annie;Ruan, Hai-Bin;Kursawe, Romy;Caprio, Sonia;Thibodeau, Jacques;Bourgeois-Daigneault, Marie-Claude;Sun, Lisha;Gao, Guangping;Bhanot, Sanjay;Jurczak, Michael J.;Green, Michael R.;Shulman, Gerald I.;Wajapeyee, Narendra
通讯作者：
Wajapeyee, Narendra
影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
DOI：
10.1002/oby.21133
发表时间：
2015-07
期刊：
Obesity (Silver Spring, Md.)
影响因子：
--
作者：
Fried SK;Lee MJ;Karastergiou K
通讯作者：
Karastergiou K
影响因子：
7.3
作者：
Kraakman MJ;Murphy AJ;Jandeleit-Dahm K;Kammoun HL
通讯作者：
Kammoun HL
影响因子：
2.4
作者：
Lee M;Kwon DY;Kim MS;Choi CR;Park MY;Kim AJ
通讯作者：
Kim AJ