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Published on: March 29, 2024
Cardiac-specific LRP6 knockout induces lipid accumulation through Drp1/CPT1b pathway in adult mice
Ying Wang1, Chao Yin1, Zhidan Chen1
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.
Insights
Low-density lipoprotein receptor-related protein 6 (LRP6) deficiency in the heart leads to lipid accumulation via the dynamin-related protein 1 (Drp1)/carnitine palmitoyltransferase 1b (CPT1b) pathway, involving c-Myc. This highlights LRP6
Area of Science:
- Cardiovascular Biology
- Metabolic Regulation
- Molecular Cardiology
Background:
- Low-density lipoprotein receptor-related protein 6 (LRP6) is crucial for heart function, with deficiency linked to dilated cardiomyopathy and heart failure.
- Previous studies noted lipid accumulation in LRP6-deficient hearts, but the underlying molecular mechanisms remained elusive.
Purpose of the Study:
- To elucidate the molecular mechanisms of lipid accumulation in hearts lacking LRP6.
- To investigate the role of fatty acid metabolism and related pathways in LRP6 deficiency-induced cardiac dysfunction.
Main Methods:
- Cardiac-specific LRP6 knockout mouse model.
- Gas chromatography-flame ionization detection/mass spectrometry (GC-FID/MS) for fatty acid analysis.
- Assessment of mitochondrial β-oxidation enzyme (CPT1b) and transcription factor (c-Myc, CTCF) expression.
- Pharmacological inhibition of dynamin-related protein 1 (Drp1).
- In vitro studies using cardiomyocytes.
Main Results:
- Cardiac LRP6 knockout elevated total fatty acids and specific medium-long-chain fatty acids (C16:0, C18:1n9, C18:2n6).
- LRP6 deficiency decreased carnitine palmitoyltransferase 1b (CPT1b) expression, coinciding with dynamin-related protein 1 (Drp1) activation.
- Drp1 inhibition improved cardiac function, reduced fatty acid accumulation, and restored CPT1b, CTCF, and c-Myc expression.
- c-Myc, but not CTCF, regulated CPT1b expression and lipid accumulation in cardiomyocytes.
Conclusions:
- Cardiac-specific LRP6 deficiency induces cardiac lipid accumulation through the Drp1/CPT1b pathway in adult mice.
- The transcription factor c-Myc plays a significant role in mediating LRP6 deficiency-induced lipid metabolism alterations.
- LRP6 is identified as a key regulator of fatty acid metabolism in the adult heart.
Abstract:
We recently reported low-density lipoprotein receptor-related protein 6 (LRP6) decreased in dilated cardiomyopathy hearts, and cardiac-specific knockout mice displayed lethal heart failure through activation of dynamin-related protein 1 (Drp1). We also observed lipid accumulation in LRP6 deficiency hearts, but the detailed molecular mechanisms are unclear. Here, we detected fatty acids components in LRP6 deficiency hearts and explored the potential molecular mechanisms. Fatty acid analysis by GC-FID/MS revealed cardiac-specific LRP6 knockout induced the higher level of total fatty acids and some medium-long-chain fatty acids (C16:0, C18:1n9 and C18:2n6) than in control hearts. Carnitine palmitoyltransferase 1b (CPT1b), a rate-limiting enzyme of mitochondrial β-oxidation in adult heart, was sharply decreased in LRP6 deficiency hearts, coincident with the activation of Drp1. Drp1 inhibitor greatly improved cardiac dysfunction and attenuated the increase in total fatty acids and fatty acids C16:0, C18:1n9 in LRP6 deficiency hearts. It also greatly inhibited the decrease in the cardiac expression of CPT1b and the transcriptional factors CCCTC-binding factor (CTCF) and c-Myc induced by cardiac-specific LRP6 knockout in mice. C-Myc but not CTCF was identified to regulate CPT1b expression and lipid accumulation in cardiomyocytes in vitro. The present study indicated cardiac-specific LRP6 knockout induced lipid accumulation by Drp1/CPT1b pathway in adult mice, and c-Myc is involved in the process. It suggests that LRP6 regulates fatty acid metabolism in adult heart.
