# Deciphering a Novel LncRNA-mediated Lipid Droplet Transport System in Human Heart

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $541,523

## Abstract

Abstract
The overarching goal of this proposal is to uncover novel HUMAN-SPECIFIC molecular mechanisms by which
human long non-coding RNA (lncRNA) HL6 facilitates lipid droplet (LD) transport in human cardiomyocytes (CMs)
and manifests a cardioprotective role against metabolic syndrome associated cardiomyopathy. ~70% energy of
adult human heart is obtained from oxidation of long chain fatty acids (FAs). Balanced lipid metabolism is crucial
for heart function. Compromised lipid metabolism have been widely observed in cardiomyopathies associated
with metabolic syndromes, such as obesity and diabetes. The distinct features of obese and diabetes associated
cardiomyopathy are increased incidence of heart failure together with extensive intramyocyte lipid droplet
accumulation. LD consists of a neutral lipid core surrounded by a phospholipid monolayer, which plays a critical
role in excess fatty acid storage and mobilization. However, overwhelmed intramyocyte LDs can cause cardiac
lipotoxicity and dysfunction in both human patients and rodent models of obesity and diabetes. Although ample
evidence suggests that LD accumulation in CMs could be due to impaired LD transport, the cellular system for
LD transport in mammalian heart remains elusive. Particularly, the human-specific LD transport system of CMs
and its implication in metabolic syndrome associated cardiomyopathy and heart failure remain unknown.
Recently, we identified a human lncRNA, Heart LncRNA 6 (HL6), which is highly and specifically expressed in
human CMs and downregulated in human type 2 diabetic myocardium. HL6 was knocked out (HL6KO) in
human iPSCs (hiPSCs) by using CRISPR/Cas-9. We found HL6 deficiency led to extensive LD
accumulation, defective LD transport to mitochondria, swollen mitochondria with impaired function, and
enhanced CM death in HL6KO hiPSC-CMs verse WT hiPSC-CMs. Intriguingly, HL6 binds LDs and
cytoskeleton in hiPSC-CMs. Additionally, transgenic HL6 overexpression significantly mitigated high fat diet
(HFD)-induced lipid accumulation and cardiac dysfunction of mouse heart. Therefore, we hypothesize that HL6
plays an indispensable role in LD transport to mitochondria in human CMs, and gain-of-HL6 manifests a
cardioprotective role against metabolic syndrome associated cardiomyopathy. Two specific aims are proposed:
Specific Aim 1: Decipher the indispensable role of HL6 in lipid droplet transport of human CMs. Specific Aim 2:
Determine the cardioprotective role of HL6 in metabolic syndrome associated cardiomyopathy.

## Key facts

- **NIH application ID:** 10520928
- **Project number:** 1R01HL160856-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Lei Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $541,523
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520928

## Citation

> US National Institutes of Health, RePORTER application 10520928, Deciphering a Novel LncRNA-mediated Lipid Droplet Transport System in Human Heart (1R01HL160856-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10520928. Licensed CC0.

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