Epigenetic Modifications in Alternative Splicing of LDLR pre-mRNA on Hypercholesterolemia Following Aerobic Exercise...

Area of Science:

• Biochemistry
• Molecular Biology
• Exercise Physiology

Background:

• Cholesterol metabolism is crucial for health, with dysregulation linked to cardiovascular disease.
• The low-density lipoprotein receptor (LDLR) plays a key role in cholesterol homeostasis.
• Alternative splicing of LDLR pre-mRNA can generate variants affecting its function.

Purpose of the Study:

• To investigate if exercise training impacts cholesterol metabolism by altering LDLR alternative splicing.
• To compare LDLR splice variants in exercise-trained versus non-trained individuals with varying cholesterol levels.
• To elucidate the role of histone modifications in exercise-induced changes in LDLR splicing.

Main Methods:

• Comparative analysis of blood lipids and LDLR splice variants in human subjects.
• RT-PCR to examine LDLR splice isoform expression in humans and mice.
• CHIP-assay to assess histone H3K36me3 modification in mouse liver.
• In vitro studies using HepG2 cells to investigate histone modification effects on LDLR splicing.

Main Results:

• Obese adults with high cholesterol exhibited higher expression of LDLR variants (LDLR-∆Exon4, LDLR-∆Exon12).
• Exercise training significantly reduced these LDLR splice variants in normal cholesterol individuals.
• High-cholesterol diet increased LDLR-∆Exon14 in mice, an effect reversed by exercise training.
• Histone modifications (H3-K36me3) were shown to influence LDLR alternative splicing in HepG2 cells.

Conclusions:

• Hypercholesterolemia is associated with increased expression of LDLR splice variants.
• Aerobic exercise training effectively prevents and reverses dyslipidemia-associated alternative splicing of LDLR pre-mRNA.
• Histone modifications play a significant role in regulating LDLR alternative splicing.