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Lin28a Regulates Pathological Cardiac Hypertrophic Growth through Pck2‐mediated Enhancement of Anabolic Synthesis
Author(s) -
Ma Hong,
Yu Shuo,
Liu Xiaojing,
Zhang Yingao,
Fakadej Thomas,
Liu Ziqing,
Yin Chaoying,
Shen Weining,
Locasale Jason W,
Taylor Joan M,
Qian Li,
Liu Jiandong
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.662.29
Subject(s) - anabolism , pathological , muscle hypertrophy , cardiac hypertrophy , regulator , transcriptome , biology , medicine , endocrinology , phenotype , pressure overload , downregulation and upregulation , microbiology and biotechnology , cancer research , gene expression , biochemistry , gene
During pathological hypertrophy, the heart undergoes extensive metabolic changes prior to the onset of structural remodeling, yet, it remains largely unexplored whether and how this metabolic remodeling could contribute to cardiac hypertrophic growth. Here, we identified the RNA‐binding protein Lin28a as a critical regulator of pathological cardiac hypertrophy and metabolic re‐patterning. Cardiac‐specific deletion of Lin28a attenuated pressure overload‐induced hypertrophic growth, cardiac dysfunction and alterations in cardiac transcriptome. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2 ) mRNA and positively modulated its level. Manipulation of Pck2 expression phenocopied hypertrophic growth phenotypes of manipulating Lin28a expression. Epistatic analysis demonstrated that Pck2 mediated, at least in part, the role of Lin28a in cardiac hypertrophic growth. Furthermore, metabolomic analyses highlighted role for Lin28a and Pck2 in promoting cardiac anabolic biosynthesis required for cell growth. Thus, our study revealed a critical role of Lin28a in the regulation of pathological cardiac hypertrophic growth through Pck2‐mediated regulation of cardiac metabolism. Support or Funding Information This study was supported by AHA 13SDG17060010, Ellison Medical Foundation (EMF) AGNS‐13 1064‐, and NIH/NHLBI R01HL128331 to L.Q., NIH/NHLBI R00 HL109079, R56HL133081, and American Heart Association (AHA) 15GRNT25530005 to J.L. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .