# The role of RNA-binding protein Lin28a in hypertrophic cardiomyopathy

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $523,184

## Abstract

Abstract
Pathological cardiac hypertrophy is a major risk factor of heart failure and sudden cardiac death, the leading
cause of mortality in the US and worldwide. Despite substantial progress in our understanding of the molecular
and physiological basis of this detrimental process, much remains to be learned. Cardiac hypertrophic response
to pathological stimuli is a complex biological process that involves transcriptional, posttranscriptional and
epigenetic regulation of the cardiac genome. RNA-binding protein (RBPs) constitutes a major layer of molecular
regulation integral to the establishment of tissue transcriptomes. The RBPs play fundamental roles during both
development and disease by regulating RNA biogenesis, structure, stability, transport and cellular localization.
Among them, Lin28a was found to control many developmental and cellular processes including pluripotency,
oncogenesis, tissue repair and metabolism via its role in increasing mRNA stability and/or translation efficiency.
Although previous studies have implicated transcriptional factors and signaling molecules in pathological cardiac
hypertrophy, the role of RBPs in this process received little attention. Through gene expression analysis, we
found that Lin28a exhibited a dynamic expression during early stage of pathological cardiac hypertrophy. Cardiac
specific deletion of Lin28a blunted pressure overload-induced cardiac hypertrophy. Likewise, in an in vitro model
of cardiac hypertrophy, knockdown of Lin28a attenuated norepinephrine (NE)-induced hypertrophy, while
overexpressing Lin28a alone was sufficient to enhance cardiomyocyte glycolysis and stimulate subsequent
cardiomyocyte hypertrophic growth. Mechanistically, we found that Lin28a directly bound to the mRNA of Pck2,
which encodes the mitochondrial phosphoenolpyruvate carboxykinase, and positively impacted its transcript
level. Additionally, manipulation of Pck2 expression phenocopied the metabolic and hypertrophic phenotypes of
manipulating Lin28a expression. Based on these observations, we hypothesize that Lin28a and its downstream
mediator Pck2 act as crucial regulators of pathological cardiac hypertrophy via their roles in regulating
cardiomyocyte metabolism. The aim of this proposal will leverage our series of unique tools, reagents, and animal
models to elucidate the molecular and cellular pathways essential for the development of pathological cardiac
hypertrophy. In doing so, we will address a central question concerning whether and how a metabolic switch to
a more glycolytic phenotype during cardiac hypertrophy could contribute to the structural remodeling.

## Key facts

- **NIH application ID:** 10204792
- **Project number:** 5R01HL139976-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jiandong Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $523,184
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10204792

## Citation

> US National Institutes of Health, RePORTER application 10204792, The role of RNA-binding protein Lin28a in hypertrophic cardiomyopathy (5R01HL139976-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10204792. Licensed CC0.

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