APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction

Author:

Park Min1,Wu Donghai2,Park Taesik3,Choi Cheol-soo4,Li Ren-Ke5,Cheng Kenneth K. Y.6,Xu Aimin6,Sweeney Gary1

Affiliation:

1. Department of Biology, York University, Toronto, Ontario, Canada;

2. Guangzhou Institute for Biomedicine and Health, Guangzhou, Guangdong, China;

3. Departement of Life Science, Gachon University, Sungnam, South Korea;

4. Korea Mouse Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea;

5. Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and

6. Department of Medicine, University of Hong Kong, Hong Kong, China

Abstract

APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1) has been established as an important mediator of insulin and adiponectin signaling. Here, we investigated the influence of transgenic (Tg) APPL1 overexpression in mice on high-fat diet (HFD)-induced cardiomyopathy in mice. Wild-type (WT) mice fed an HFD for 16 wk showed cardiac dysfunction, determined by echocardiography, with decreased ejection fraction, decreased fractional shortening, and increased end diastolic volume. HFD-fed APPL1 Tg mice were significantly protected from this dysfunction. Speckle tracking echocardiography to accurately assess cardiac tissue deformation strain and wall motion also indicated dysfunction in WT mice and a similar improvement in Tg vs. WT mice on HFD. APPL1 Tg mice had less HFD-induced increase in circulating nonesteridied fatty acid levels and myocardial lipid accumulation. Lipidomic analysis using LC-MS-MS showed HFD significantly increased myocardial contents of distinct ceramide, sphingomyelin, and diacylglycerol (DAG) species, of which increases in C16:0 and C18:0 ceramides plus C16:0 and C18:1 DAGs were attenuated in Tg mice. A glucose tolerance test indicated less peripheral insulin resistance in response to HFD in Tg mice, which was also apparent by measuring cardiac Akt phosphorylation and cardiomyocyte glucose uptake. In summary, APPL1 Tg mice exhibit improved peripheral metabolism, reduced cardiac lipotoxicity, and improved insulin sensitivity. These cellular effects contribute to protection from HFD-induced cardiomyopathy.

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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