Lightbourne Marissa, Wolska Anna, Abel Brent S, Rother Kristina I, Walter Mary, Kushchayeva Yevgeniya, Auh Sungyoung, Shamburek Robert D, Remaley Alan T, Muniyappa Ranganath, Brown Rebecca J
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
J Endocr Soc. 2020 Dec 4;5(2):bvaa191. doi: 10.1210/jendso/bvaa191. eCollection 2021 Feb 1.
Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood.
Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin.
Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma.
Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 ( < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma ( < .0001), which did not change after metreleptin.
Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.
脂肪营养不良综合征会导致高甘油三酯血症，使用米泊明治疗瘦素可改善这种情况。导致高甘油三酯血症的机制以及米泊明治疗后的改善情况尚未完全了解。
确定在健康对照者以及脂肪营养不良患者中，循环脂蛋白脂肪酶（LPL）调节剂与米泊明治疗前后高甘油三酯血症之间的关系。
对脂肪营养不良患者（全身性脂肪营养不良3例；部分性脂肪营养不良11例）与年龄/性别匹配的健康对照者（28例）进行横断面比较，并对患者在接受米泊明治疗2周和6个月前后进行纵向分析。该研究在美国国立卫生研究院（马里兰州贝塞斯达）进行。观察指标包括LPL刺激剂载脂蛋白（apo）C-II和apoA-V以及抑制剂apoC-III和血管生成素样蛋白（ANGPTLs）3、4和8；血浆对LPL的体外激活作用。
脂肪营养不良患者存在高甘油三酯血症，与对照组相比，除ANGPTL4外，所有LPL刺激剂和抑制剂水平均较高，ANGPTL8高300多倍，apoC-III高4倍，apoC-II高3.5倍，apoA-V高1.9倍，ANGPTL3高1.6倍（所有P< .05）。基线时，除ANGPLT4外，所有LPL调节剂均与甘油三酯呈正相关。米泊明在2周和6个月后降低了apoC-II和apoC-III，在6个月后降低了ANGPTL8（所有P< 0.05）。与高甘油三酯血症对照血浆相比（< .0001），脂肪营养不良患者的血浆导致更高的体外LPL激活，米泊明治疗后未发生变化。
LPL抑制剂apoC-III和ANGPTL8升高可能导致脂肪营养不良中的高甘油三酯血症，并可能介导米泊明治疗后循环和肝脏甘油三酯的降低。因此，这些是降低这些患者甘油三酯治疗的有力候选药物。
