Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia.
Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia.
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DOI：
10.1002/hep.25580
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发表时间：
2012-06
期刊：
影响因子：
13.5
通讯作者：
Williams, Kevin Jon
中科院分区：
文献类型：
--
作者：
Hassing, H. Carlijne;Mooij, Hans;Guo, Shuling;Monia, Brett P.;Chen, Keyang;Kulik, Wim;Dallinga-Thie, Geesje M.;Nieuwdorp, Max;Stroes, Erik S. G.;Williams, Kevin Jon
2型糖尿病（T2 DM）损害致动脉粥样硬化性餐后富甘油三酯脂蛋白（TRL）的肝脏清除。我们最近报道，T2 DM db/db小鼠的肝脏显著过表达葡萄糖胺-6-O-内硫酸酯酶-2（SULF 2），这是一种从硫酸乙酰肝素蛋白聚糖（HSPG）中去除6-O硫酸酯基团并抑制培养肝细胞摄取TRL的酶。在本研究中，我们评估了T2 DM小鼠体内Sulf 2抑制是否可以纠正其餐后血脂异常。鉴定了靶向Sulf 2的选择性第二代反义寡核苷酸（ASO）。Db/db小鼠用Sulf 2阿索（20或50 mg/kg/周）、非靶阿索或磷酸盐缓冲盐水（PBS）治疗5周。向db/db小鼠施用Sulf 2阿索抑制肝脏Sulf 2 mRNA表达70- 80%，即，降低至非糖尿病db/m小鼠中的水平，并增加肝HSPG中三硫酸化二糖与二硫酸化二糖的比率（p<0.05）。从接受非靶向阿索的db/db小鼠中分离的肝细胞显示VLDL结合显著受损，这在接受Sulf 2阿索的db/db小鼠中完全纠正。Sulf 2阿索使随机、非空腹血浆甘油三酯（TG）水平降低50%，达到非糖尿病值。最重要的是，Sulf 2阿索治疗使玉米油灌胃后db/db小鼠的血浆TG波动变平（非靶阿索的iAUC为1500±470（mg/dL）·h，Sulf 2阿索为160±40（mg/dL）·h（p<0.01））。尽管T2 DM小鼠存在广泛的代谢紊乱，但抑制单一失调分子SULF 2可使其肝细胞的VLDL结合能力正常化，并消除餐后高脂血症。这些发现提供了关键的体内概念验证，以支持Sulf 2抑制作为改善代谢性血脂异常的有吸引力的策略。
Type 2 diabetes mellitus (T2DM) impairs hepatic clearance of atherogenic postprandial triglyceride-rich lipoproteins (TRL). We recently reported that livers from T2DM db/db mice markedly overexpress glucosamine-6-O-endosulfatase-2 (SULF2), an enzyme that removes 6-O sulfate groups from heparan sulfate proteoglycans (HSPGs) and suppresses uptake of TRLs by cultured hepatocytes. In the present study, we evaluated whether Sulf2 inhibition in T2DM mice in vivo could correct their postprandial dyslipidemia. Selective second-generation antisense oligonucleotides (ASOs) targeting Sulf2 were identified. Db/db mice were treated for 5 weeks with Sulf2 ASO (20 or 50 mg/kg per week), non-target ASO, or phosphate buffered saline (PBS). Administration of Sulf2 ASO to db/db mice suppressed hepatic Sulf2 mRNA expression by 70–80%, i.e., down to levels in non-diabetic db/m mice, and increased the ratio of tri- to di-sulfated disaccharides in hepatic HSPGs (p<0.05). Hepatocytes isolated from db/db mice on non-target ASO exhibited a significant impairment in VLDL binding that was entirely corrected in db/db mice on Sulf2 ASO. Sulf2 ASO lowered the random, non-fasting plasma triglyceride (TG) levels by 50%, achieving non-diabetic values. Most importantly, Sulf2 ASO treatment flattened the plasma TG excursions in db/db mice after corn-oil gavage (iAUC 1500±470 (mg/dL)·h for non-target ASO versus 160±40 (mg/dL)·h for Sulf2 ASO (p<0.01). Despite extensive metabolic derangements in T2DM mice, inhibition of a single dysregulated molecule, SULF2, normalizes the VLDL-binding capacity of their hepatocytes and abolishes postprandial hypertriglyceridemia. These findings provide a key proof-of-concept in vivo to support Sulf2 inhibition as an attractive strategy to improve metabolic dyslipidemia.
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发表时间：
2006-09-01
影响因子：
4.5
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