期刊
JOURNAL OF THE ENDOCRINE SOCIETY
卷 5, 期 2, 页码 -出版社
ENDOCRINE SOC
DOI: 10.1210/jendso/bvaa191
关键词
lipodystrophy; leptin; hypertriglyceridemia; lipoprotein lipase; apolipoprotein; angiopoietin like protein
资金
- National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health
- National Heart, Lung, and Blood Institute at the National Institutes of Health
Patients with lipodystrophy exhibit hypertriglyceridemia and elevated levels of LPL modulators, which can be reduced after metreleptin treatment. Elevations in LPL inhibitors such as apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and reductions in these factors may mediate improvements in triglyceride levels with metreleptin therapy.
Context: Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. Objective: Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Methods: 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. Results: 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 (P < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoCIII 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 (P < .0001), which did not change after metreleptin. Conclusion: 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.
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