Effect of Leptin Replacement on PCSK9 in ob/ob Mice and Female Lipodystrophic Patients.

Autor:	Levenson AE; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115., Haas ME; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115., Miao J; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115., Brown RJ; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115., de Ferranti SD; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115., Muniyappa R; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115., Biddinger SB; Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2016 Apr; Vol. 157 (4), pp. 1421-9. Date of Electronic Publication: 2016 Jan 29.
DOI:	10.1210/en.2015-1624
Abstrakt:	Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases low-density lipoprotein (LDL) clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for 4 days via sc osmotic pumps (∼24 μg/d). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes. In male mice, leptin suppressed PCSK9 but had no effect on plasma triglycerides or cholesterol. In female mice, leptin suppressed plasma triglycerides and cholesterol but had no effect on plasma PCSK9. In parallel, we treated female lipodystrophic patients (8 females, ages 5-23 y) with sc metreleptin injections (∼4.4 mg/d) for 4-6 months. In this case, leptin reduced plasma PCSK9 by 26% (298 ± 109 vs 221 ± 102 ng/mL; n = 8; P = .008), and the change in PCSK9 was correlated with a decrease in LDL cholesterol (r(2) = 0.564, P = .03). In summary, in leptin-deficient ob/ob mice, the effects of leptin on PCSK9 and plasma lipids appeared to be independent of one another and strongly modified by sex. On the other hand, in lipodystrophic females, leptin treatment reduced plasma PCSK9 in parallel with LDL cholesterol.
Databáze:	MEDLINE
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