Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Obesity (Silver Spring). 2014 May;22(5):1309-16. doi: 10.1002/oby.20682. Epub 2014 Jan 9.
Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM was investigated.
Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1,316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype.
Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; P = 0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (P < 0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P < 0.05) and retinyl esters levels (P < 0.001).
These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM.
硫酸酯酶-2（SULF2）是一种肝素硫酸酯修饰酶，在肥胖、2 型糖尿病（T2DM）db/db 小鼠中过度表达，强烈导致甘油三酯（TG）水平升高。然而，人类的数据尚缺乏。本研究旨在研究人类肝脏 SULF2 表达和 SULF2 基因变异与肥胖和/或 T2DM 患者 TG 代谢的关系。
分析了 121 名肥胖患者的肝活检组织，以研究肝 SULF2 mRNA 水平与血浆 TG 之间的关系。在 210 名血脂异常的肥胖 T2DM 患者中评估了 7 个 SULF2 标签 SNP 与 TG 水平之间的关联。在 1316 名独立的肥胖 T2DM 患者中复制了阳性发现。根据 SULF2 基因型对 29 名肥胖 T2DM 患者进行餐后 TRL 清除率评估。
在肥胖患者中，肝 SULF2 表达与空腹血浆 TG 显著相关（r = 0.271；P = 0.003）。SULF2 rs2281279（A>G）SNP 可重复地与肥胖 T2DM 患者空腹血浆 TG 水平降低相关（P < 0.05）。携带 minor G 等位基因与餐后血浆 TG（P < 0.05）和视黄酯水平（P < 0.001）降低相关。
这些发现表明 SULF2 可能是肥胖和 T2DM 致动脉粥样硬化性血脂异常的潜在治疗靶点。
