Related Experiment Video
Updated: Jan 9, 2026
Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
Published on: January 31, 2025
HSPA12A impairs lipophagy to exaggerate septic cardiomyopathy by promoting MTOR's competition against LC3-II in
Yunfan Li1, Shijiang Liu1, Xinxu Min1
1Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Accumulation of lipid droplets (LDs) in cardiomyocytes contributes to developmentof septic cardiomyopathy, a fatal complication of critical illness in patients.Lipophagy is a selective autophagic mechanism for LD degradation. This processis inhibited by MTOR, but is activated by PNPLA2 via its binding with LC3-II toform LD-containing autophagosomes. However, optimum lipophagic interventions tomanage septic cardiomyopathy have not been developed, thus furtherinvestigation is required to identify novel regulators of lipophagy in theseptic heart. HSPA12A (heat shockprotein 12A) encodes an atypical member of the HSPA/HSP70family. Here, we report that sepsis decreased HSPA12Aexpression in cardiomyocytes, whereas cardiomyocyte-specific HSPA12Aoverexpression aggravated sepsis-induced cardiomyocyte death and cardiacdysfunction in mice. Notably, HSPA12A promoted sepsis-induced LD accumulationin cardiomyocytes. By contrast, HSPA12A inhibited lipophagy in septiccardiomyocytes, as reflected by a decreased level of LD-containing autophagosomes,a reduced content of LC3-II, and an increased level of SQSTM1/p62. In-depthmolecular analysis revealed that HSPA12A increased phosphorylation of MTOR andthus its binding to PNPLA2 on LDs. MTOR thereby competed against LC3-II inbinding with PNPLA2 to suppress LD-containing autophagosome formation subsequentlyimpairing lipophagy and ultimately promoting cardiomyocyte death to exaggerate septiccardiomyopathy. We demonstrated that MTOR competed against LC3-II in bindingwith PNPLA2 to inhibit lipophagy and also identified HSPA12A as a driver ofthis competition with MTOR to impair lipophagy for exaggerating septic cardiomyopathy. Strategiesthat inhibit HSPA12A in cardiomyocytes might be a potential therapeuticintervention for septic cardiomyopathy.
Insights
Heat shock protein 12A (HSPA12A) worsens septic cardiomyopathy by inhibiting lipophagy, the process of degrading lipid droplets in heart cells. Inhibiting HSPA12A may offer a therapeutic strategy for this condition.
Area of Science:
- Cardiology
- Cell Biology
- Molecular Medicine
Background:
- Septic cardiomyopathy, a fatal complication of critical illness, involves lipid droplet accumulation in cardiomyocytes.
- Lipophagy, the degradation of lipid droplets, is crucial for managing this condition but is poorly understood in the septic heart.
- Current lipophagic interventions for septic cardiomyopathy are suboptimal, necessitating the identification of novel regulators.
Purpose of the Study:
- To investigate the role of heat shock protein 12A (HSPA12A) in sepsis-induced cardiomyocyte dysfunction and lipid metabolism.
- To elucidate the molecular mechanisms by which HSPA12A influences lipophagy in the context of septic cardiomyopathy.
- To identify HSPA12A as a potential therapeutic target for septic cardiomyopathy.
Main Methods:
- Utilized mouse models with cardiomyocyte-specific HSPA12A overexpression.
- Assessed cardiomyocyte death, cardiac function, and lipid droplet accumulation under septic conditions.
- Analyzed lipophagy markers, including LC3-II, SQSTM1/p62, and autophagosome formation.
- Investigated the interaction between HSPA12A, MTOR, PNPLA2, and LC3-II through molecular analysis.
Main Results:
- Sepsis decreased endogenous HSPA12A expression in cardiomyocytes.
- Cardiomyocyte-specific HSPA12A overexpression exacerbated sepsis-induced cardiomyocyte death and cardiac dysfunction.
- HSPA12A promoted lipid droplet accumulation and inhibited lipophagy by decreasing LC3-II and autophagosome formation.
- HSPA12A enhanced MTOR phosphorylation, promoting its binding to PNPLA2 and competing with LC3-II, thereby suppressing lipophagy.
Conclusions:
- HSPA12A exacerbates septic cardiomyopathy by impairing lipophagy through MTOR-mediated inhibition of autophagosome formation.
- HSPA12A acts as a key regulator, driving competition between MTOR and LC3-II for PNPLA2 binding, ultimately hindering lipophagy.
- Inhibiting HSPA12A in cardiomyocytes presents a potential therapeutic avenue for managing septic cardiomyopathy.
Related Concept Videos
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:20The JAK-STAT Signaling Pathway
01:22Lysosomal Hydrolases