SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr(-/-) type 1 diabetic mice.
SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr(-/-) type 1 diabetic mice.
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DOI：
10.1016/j.atherosclerosis.2018.02.028
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发表时间：
2018-04
期刊：
影响因子：
5.3
通讯作者：
Nagareddy PR
中科院分区：
文献类型：
--
作者：
Al-Sharea A;Murphy AJ;Huggins LA;Hu Y;Goldberg IJ;Nagareddy PR
白细胞增多症，特别是单核细胞增多症，已经显示在糖尿病和非糖尿病小鼠模型中促进动脉粥样硬化。我们以前的研究表明，高血糖独立地促进单核细胞增多，并损害动脉粥样硬化的解决。由于慢性糖尿病患者经常发生血脂异常，动脉粥样硬化的风险也增加，我们试图研究在严重高脂血症的情况下，控制血糖如何影响动脉粥样硬化的发展。在低密度脂蛋白受体（Ldlr）敲除（Ldlr−/−）小鼠中使用链脲佐菌素（STZ）诱导糖尿病，然后喂食高胆固醇饮食4周。对照组和糖尿病小鼠在饮食期间接受溶媒或钠葡萄糖协同转运蛋白抑制剂（SGLT 2 i、根皮苷或达格列净）给药。诱导糖尿病导致血浆胆固醇（TC）和甘油三酯（TG）水平急剧增加。这些小鼠还表现出循环单核细胞和中性粒细胞数量增加。单核细胞增多由骨髓中祖细胞增殖增加驱动。通过SGLT 2 i治疗更严格地控制血糖不仅可减少单核细胞增多和动脉粥样硬化，还可改善血浆脂蛋白谱。有趣的是，脂蛋白谱的改善不是由于TG合成减少或通过低密度脂蛋白受体相关蛋白（Lrp）1或清道夫受体B类成员（Scarb 1）途径清除，而是可能由肝脏中硫酸肝素蛋白聚糖（HSPG）依赖性清除机制介导。肝脏的进一步检查显示胆汁酸转运蛋白（Abcg 5，Abcg 8）和细胞色素P450酶在肝脏胆固醇清除中的重要作用。这些数据表明，在糖尿病中更严格的血糖控制可以改善脂蛋白清除率（不包括Ldlr），可能是通过HSPG和胆汁酸途径，并且对动脉粥样硬化具有总体净积极作用。
Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia. Diabetes was induced using streptozotocin (STZ) in low density lipoprotein receptor (Ldlr) knockout (Ldlr−/−) mice after which they were fed a high-cholesterol diet for 4 weeks. Control and diabetic mice were treated with vehicle or sodium glucose cotransporter inhibitor (SGLT2i, Phlorizin or Dapagliflozin) for the duration of the diet. Induction of diabetes resulted in a dramatic increase in plasma cholesterol (TC) and triglyceride (TG) levels. These mice also exhibited an increased number of circulating monocytes and neutrophils. Monocytosis was driven by increased proliferation of progenitor cells in the bone marrow. Tighter glycemic control by SGLT2i treatment not only reduced monocytosis and atherosclerosis but also improved plasma lipoprotein profile. Interestingly, improved lipoprotein profile was not due to decreased TG synthesis or clearance via low density lipoprotein receptor-related protein (Lrp) 1 or scavenger receptor class B member (Scarb1) Pathways, but likely mediated by heparin sulfate proteoglycans (HSPG)-dependent clearance mechanisms in the liver. Further examination of the liver revealed an important role for bile acid transporters (Abcg5, Abcg8) and cytochrome P450 enzymes in the clearance of hepatic cholesterol. These data suggest that tighter glycemic control in diabetes can improve lipoprotein clearance exclusive of Ldlr, likely via HSPG and bile acid pathways and, has an overall net positive effect on atherosclerosis.
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影响因子：
7.7
作者：
Parathath S;Grauer L;Huang LS;Sanson M;Distel E;Goldberg IJ;Fisher EA
通讯作者：
Fisher EA
DOI：
10.1161/atvbaha.113.301637
发表时间：
2013-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Foley EM;Gordts PLSM;Stanford KI;Gonzales JC;Lawrence R;Stoddard N;Esko JD
通讯作者：
Esko JD
DOI：
10.1016/j.bbalip.2005.06.001
发表时间：
2005-08-15
影响因子：
4.8
作者：
Murphy, C;Parini, P;Gåfvels, M
通讯作者：
Gåfvels, M
影响因子：
15.9
作者：
Potteaux, Stephane;Gautier, Emmanuel L.;Randolph, Gwendalyn J.
通讯作者：
Randolph, Gwendalyn J.
影响因子：
15.9
作者：
CHAIT, A;BIERMAN, EL;ALBERS, JJ
通讯作者：
ALBERS, JJ