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Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy
Hongyi Zhou, … , Huabo Su, Weiqin Chen
Hongyi Zhou, … , Huabo Su, Weiqin Chen
Published June 11, 2019
Citation Information: JCI Insight. 2019;4(14):e129781. https://doi.org/10.1172/jci.insight.129781.
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Research Article Cardiology Metabolism

Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy

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Abstract

Mutations in the BSCL2 gene underlie human type 2 Berardinelli-Seip congenital lipodystrophy (BSCL2) disease. Global Bscl2–/– mice recapitulate human BSCL2 lipodystrophy and results in the development of insulin resistance and hypertrophic cardiomyopathy. The pathological mechanisms underlying the development of lipodystrophy and cardiomyopathy in BSCL2 are controversial. Here we report that Bscl2–/– mice develop cardiac hypertrophy because of increased basal IGF1 receptor–mediated (IGF1R-mediated) PI3K/AKT signaling. Bscl2–/– hearts exhibited increased adipose triglyceride lipase (ATGL) protein stability and expression causing drastic reduction of glycerolipids. Excessive fatty acid oxidation was overt in Bscl2–/– hearts, partially attributing to the hyperacetylation of cardiac mitochondrial proteins. Intriguingly, pharmacological inhibition or genetic inactivation of ATGL could rescue adipocyte differentiation and lipodystrophy in Bscl2–/– cells and mice. Restoring a small portion of fat mass by ATGL partial deletion in Bscl2–/– mice not only reversed the systemic insulin resistance, but also ameliorated cardiac protein hyperacetylation, normalized cardiac substrate metabolism, and improved contractile function. Collectively, our study uncovers pathways underlying lipodystrophy-induced cardiac hypertrophy and metabolic remodeling and pinpoints ATGL as a downstream target of BSCL2 in regulating the development of lipodystrophy and its associated cardiomyopathy.

Authors

Hongyi Zhou, Xinnuo Lei, Yun Yan, Todd Lydic, Jie Li, Neal L. Weintraub, Huabo Su, Weiqin Chen

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Figure 1

Elevated basal IGF1R-mediated PI3K/AKT signaling in hypertrophic Bscl2–/– hearts.

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Elevated basal IGF1R-mediated PI3K/AKT signaling in hypertrophic Bscl2–/...
(A and B) Transcriptome and pathway analyses of differentially expressed (DE) genes and heatmap from DE genes related to PI3K/AKT signaling in left ventricles of 10-week-old female Bscl2–/– mice after a 4-hour fast (n = 4 pooled from 3 animals each). (C–G) Western blot and quantification of pAKT at Ser473, pGSK3β at Ser9, pS6K at Thr389, and pIGF1Rβ/IRβ at Tyr1158/Tyr1162/Tyr1163 in hearts (n = 5/group). (H) Immunoprecipitation of cardiac IGF1Rβ detects enhanced tyrosine phosphorylation of IGF1Rβ. Representative Western blot is shown. n = 5/group. (I) Plasma IGF1 levels (n = 11/group). For C–I, ad libitum–fed 3-month-old male Bsc2+/+ and Bscl2–/– mice were used. *P < 0.05 by unpaired t test.

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