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Cardiac-specific LRP6 knockout induces lipid accumulation through Drp1/CPT1b pathway in adult mice

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Abstract

We recently reported low-density lipoprotein receptor-related protein 6 (LRP6) decreased in dilated cardiomyopathy hearts, and cardiac-specific knockout mice displayed lethal heart failure through activation of dynamin-related protein 1 (Drp1). We also observed lipid accumulation in LRP6 deficiency hearts, but the detailed molecular mechanisms are unclear. Here, we detected fatty acids components in LRP6 deficiency hearts and explored the potential molecular mechanisms. Fatty acid analysis by GC-FID/MS revealed cardiac-specific LRP6 knockout induced the higher level of total fatty acids and some medium-long-chain fatty acids (C16:0, C18:1n9 and C18:2n6) than in control hearts. Carnitine palmitoyltransferase 1b (CPT1b), a rate-limiting enzyme of mitochondrial β-oxidation in adult heart, was sharply decreased in LRP6 deficiency hearts, coincident with the activation of Drp1. Drp1 inhibitor greatly improved cardiac dysfunction and attenuated the increase in total fatty acids and fatty acids C16:0, C18:1n9 in LRP6 deficiency hearts. It also greatly inhibited the decrease in the cardiac expression of CPT1b and the transcriptional factors CCCTC-binding factor (CTCF) and c-Myc induced by cardiac-specific LRP6 knockout in mice. C-Myc but not CTCF was identified to regulate CPT1b expression and lipid accumulation in cardiomyocytes in vitro. The present study indicated cardiac-specific LRP6 knockout induced lipid accumulation by Drp1/CPT1b pathway in adult mice, and c-Myc is involved in the process. It suggests that LRP6 regulates fatty acid metabolism in adult heart.

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Acknowledgments

We thank Prof. Bart O. Williams (Van Andel Research Institute, Michigan, USA) and Dr. Mercy Davidson (Columbia University, New York, USA) for generously providing LRP6fl/fl mice and the AC16 cells respectively.

Funding

This work was supported by the National Natural Science Foundation of China (81570353 to Hui Gong; 31430039 to Yunzeng Zou).

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Author notes

  1. Ying Wang

    Present address: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China

Authors and Affiliations

  1. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China

    Chao Yin, Zhidan Chen, Yang Li, Yan Zou, Xiang Wang, Feizhen Wu, Guoping Zhang, Chunjie Yang, Yunzeng Zou & Hui Gong

  2. State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Sciences, International Centre for Molecular Phenomics, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, 200438, China

    Yanpeng An & Huiru Tang

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  1. Ying Wang
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Contributions

Y.W: performed the majority of the experiments and analyzed data. C.Y, Y.Z, Z.C: aided molecular experiments. X.W and Y.L: performed echocardiographic analysis. A.P and H.T: performed fatty acid component analysis. F.W: analyzed transcriptional factors with database. Y.C and G.Z: provided materials. Y.Z.: provided funding. H.G: conceived the study, analyzed the data, drafted and revised the manuscript, and provided funding.

Corresponding authors

Correspondence to Yunzeng Zou or Hui Gong.

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The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance the ethical standards of Fudan University, Shanghai, China, and with local animal ethics committee approval.

This article does not contain any studies with human participants performed by any of the authors. AC16 cells (human cardiomyocyte cell line) in the present study were from Dr. Mercy Davidson (Columbia University, New York, USA), and MTA (Material Transfer Agreement) has been signed between us (Permit no. 46327).

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Wang, Y., Yin, C., Chen, Z. et al. Cardiac-specific LRP6 knockout induces lipid accumulation through Drp1/CPT1b pathway in adult mice. Cell Tissue Res 380, 143–153 (2020). https://doi.org/10.1007/s00441-019-03126-3

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