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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Type 2 diabetes in mice induces hepatic overexpression of sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins.
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Type 2 diabetes in mice induces hepatic overexpression of sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins.

机译：小鼠的2型糖尿病会诱导肝脏硫酸酯酶2的过表达，硫酸酯酶2是一种抑制残余脂蛋白摄取的新因子。

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Type 2 diabetes mellitus (T2DM) impairs hepatic clearance of atherogenic postprandial remnant lipoproteins. Our work and that of others have identified syndecan-1 heparan sulfate proteoglycans (HSPGs) as remnant lipoprotein receptors. Nevertheless, defects in the T2DM liver have not been molecularly characterized, and neither has the correction that occurs upon caloric restriction. We used microarrays to compare expression of proteoglycan-related genes in livers from control db/m mice; obese, T2DM db/db littermates fed ad libitum (AL); and db/db mice pair-fed to match the intake of db/m mice. Surprisingly, the arrays identified only one gene whose dysregulation by T2DM would disrupt HSPG structure: the heparan sulfate glucosamine-6-O-endosulfatase-2 (Sulf2). SULF2 degrades HSPGs by removing 6-O sulfate groups, but had no previously known role in diabetes or lipoprotein biology. Follow-up quantitative polymerase chain reaction assays revealed a striking 11-fold induction of Sulf2 messenger RNA in the livers of AL T2DM mice compared with controls. Immunoblots demonstrated induction of SULF2 in AL livers, with restoration toward normal in livers from pair-fed db/db mice. Knockdown of SULF2 in cultured hepatocytes doubled HSPG-mediated catabolism of model remnant lipoproteins. Notably, co-immunoprecipitations revealed a persistent physical association of SULF2 with syndecan-1. To identify mechanisms of SULF2 dysregulation in T2DM, we found that advanced glycosylation end products provoked a 10-fold induction in SULF2 expression by cultured hepatocytes and an approximately 50% impairment in their catabolism of remnants and very low-density lipoprotein, an effect that was entirely reversed by SULF2 knockdown. Adiponectin and insulin each suppressed SULF2 protein in cultured liver cells and in murine livers in vivo, consistent with a role in energy flux. Likewise, both hormones enhanced remnant lipoprotein catabolism in vitro. Conclusion: SULF2 is an unexpected suppressor of atherogenic lipoprotein clearance by hepatocytes and an attractive target for inhibition.
机译：2型糖尿病（T2DM）损害肝动脉粥样硬化餐后残余脂蛋白的清除率。我们的工作和其他人的工作已经确定了syndecan-1硫酸乙酰肝素蛋白聚糖（HSPG）作为残余脂蛋白受体。然而，T2DM肝脏中的缺陷尚无分子特征，也没有热量限制时发生的校正。我们使用微阵列比较了对照db / m小鼠肝脏中蛋白聚糖相关基因的表达;肥胖，随意喂养T2DM db / db同窝仔;和db / db小鼠配对喂养以匹配db / m小鼠的摄入量。出乎意料的是，这些阵列仅鉴定出一种基因，该基因的T2DM失调会破坏HSPG结构：硫酸乙酰肝素氨基葡萄糖6-O-硫酸内切酶2（Sulf2）。 SULF2通过除去6-O硫酸基团降解HSPG，但在糖尿病或脂蛋白生物学中以前没有已知作用。后续的定量聚合酶链反应分析显示，与对照组相比，AL T2DM小鼠肝脏中Sulf2 Messenger RNA的引人注目的11倍引人注目。免疫印迹法证明，AL肝脏会诱导SULF2的产生，而成对喂养的db / db小鼠的肝脏会恢复正常。敲除培养的肝细胞中的SULF2，可使HSPG介导的模型残余脂蛋白分解代谢增加一倍。值得注意的是，共同免疫沉淀显示SULF2与syndecan-1之间存在持久的物理联系。为了确定T2DM中SULF2失调的机制，我们发现先进的糖基化终产物在培养的肝细胞中引起了SULF2表达的10倍诱导，并在残余物和非常低密度的脂蛋白的分解代谢中造成了大约50％的损伤。完全被SULF2组合击倒。脂联素和胰岛素各自在体内培养的肝细胞和鼠肝中抑制了SULF2蛋白，这与能量通量的作用一致。同样，两种激素在体外均可增强残余脂蛋白的分解代谢。结论：SULF2是肝细胞对动脉粥样硬化性脂蛋白清除的意外抑制物，并且是抑制作用的诱人靶标。

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