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Lin28a Regulates Pathological Cardiac Hypertrophic Growth through Pck2‐mediated Enhancement of Anabolic Synthesis

Hong Ma,Shuo Yu,Xiaojing Liu,Yingao Zhang,Thomas Fakadej,Ziqing Liu,C. Yin,Weining Shen,J. Locasale,Joan M Taylor,Li Qian,Jiandong Liu

Published 2019 in Circulation

ABSTRACT

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.

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