Missense variant in insulin receptor (Y1355H) segregates in family with fatty liver disease.
Missense variant in insulin receptor (Y1355H) segregates in family with fatty liver disease.
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胰岛素受体（Y1355H）的错义变体在患有脂肪肝病的家族中分离。
DOI：
10.1016/j.molmet.2021.101299
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发表时间：
2021-11
影响因子：
8.1
通讯作者：
Cohen JC
中科院分区：
文献类型：
--
作者：
Luo F;Xing C;Asrani SK;Li S;Liang G;Hobbs HH;Cohen JC
通过外显子组测序，在一个四代脂肪肝（FLD）家族的受影响成员中鉴定出胰岛素受体（INSR）胞质结构域的错义变体。该变体（rs766457461，c.4063T>C，p.Y1355H）导致组氨酸取代酪氨酸，该酪氨酸在体外响应胰岛素刺激时发生自磷酸化。由于胰岛素促进肝细胞中的脂肪生成，我们假设该变异与家族中的FLD有因果关系。为了验证这一假设，我们使用CRISPR/Cas9技术将小鼠INSR中相应的酪氨酸替换为组氨酸（Y1345 H）。通过INSR或AKT水平的磷酸化或胰岛素应答转录因子SREBP-1c的活化评估，未发现肝脏胰岛素信号传导存在显著差异。喂食普通饲料或富含脂肪、蔗糖或果糖饲料的Insr 1345 H/H小鼠的葡萄糖耐量和肝脏甘油三酯（TG）含量与WT同窝小鼠无显著差异。因此，我们在小鼠中的研究未能支持INSR（Y1355 H）与家族中的FLD有因果关系或该残基的磷酸化改变肝脏TG代谢的观点。我们发现了一个胰岛素受体（INSR）（Y1355 H）的错义变异体，它与家族性脂肪肝疾病分离。使用CRISPR建立表达INSR（Y1355 H）的小鼠。INSR（Y1355 H）小鼠的肝脏TG含量与喂食普通饲料、高脂肪或高蔗糖饲料的同窝对照小鼠无差异。
A missense variant in the cytoplasmic domain of the insulin receptor (INSR) was identified by exome sequencing in affected members of a four-generation family with fatty liver disease (FLD). The variant (rs766457461, c.4063T>C, p.Y1355H) results in the substitution of histidine for a tyrosine that undergoes autophosphorylation in response to insulin stimulation in vitro. Because insulin promotes lipogenesis in hepatocytes, we hypothesized that the variant was causally linked to FLD in the family. To test this hypothesis, we used CRISPR/Cas9 technology to replace the corresponding tyrosine in mouse INSR with histidine (Y1345H). No significant differences were found in hepatic insulin signaling, as assessed by phosphorylation of INSR or AKT levels or in activation of the insulin-responsive transcription factor SREBP-1c. Glucose tolerance and hepatic triglyceride (TG) content in Insr1345H/H mice fed a chow diet or diets rich in fat, sucrose or fructose did not differ significantly from WT littermates. Thus, our studies in mice failed to support the notion that INSR (Y1355H) is causally related to FLD in the family or that phosphorylation of this residue alters hepatic TG metabolism. We identified a missense variant in insulin receptor (INSR) (Y1355H) that segregates with fatty liver disease in family. Mice expressing INSR(Y1355H) were established using CRISPR. The hepatic TG content of INSR(Y1355H) mice did not differ from that of their littermate controls fed on a chow, high-fat, or high-sucrose diet.
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影响因子：
29
作者：
Yecies JL;Zhang HH;Menon S;Liu S;Yecies D;Lipovsky AI;Gorgun C;Kwiatkowski DJ;Hotamisligil GS;Lee CH;Manning BD
通讯作者：
Manning BD
DOI：
10.1073/pnas.1901867116
发表时间：
2019-04-09
影响因子：
11.1
作者：
Fang, Fei;Shi, Xuanming;Liang, Guosheng
通讯作者：
Liang, Guosheng
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
9.8
作者：
Buzzetti, Elena;Pinzani, Massimo;Tsochatzis, Emmanuel A.
通讯作者：
Tsochatzis, Emmanuel A.