Metabonomic Changes Associated with Atherosclerosis Progression for LDLR(-/-) Mice

Area of Science:

• Cardiovascular Research
• Metabolomics
• Systems Biology

Background:

• Hyperlipidemia-induced atherosclerosis is a major cause of cardiovascular disease.
• Understanding dynamic metabolic changes is crucial for elucidating atherosclerosis pathogenesis.
• Lipid-modulating lipoprotein lipase gene knockout (LDLR-/-) mice are a model for diet-induced atherosclerosis.

Purpose of the Study:

• To comprehensively analyze dynamic metabonomic alterations in multiple biological matrices during diet-induced atherosclerosis progression and reversal in LDLR(-/-) mice.
• To integrate multi-omics data (metabolomics, gene expression, clinical chemistry, histopathology) for a systems-level understanding.
• To identify key metabolic pathways and microbial functions involved in atherosclerosis.

Main Methods:

• Utilized LDLR(-/-) mice fed a Western-type diet (WD) for 12 weeks, followed by a switch to a normal diet.
• Employed Nuclear Magnetic Resonance (NMR) and Gas Chromatography-Flame Ionization Detection/Mass Spectrometry (GC-FID/MS) for metabonomic profiling of plasma, urine, liver, kidney, and myocardial tissues.
• Integrated metabonomic data with gene expression, clinical chemistry, and histopathological analyses.

Main Results:

• WD induced aortic lesions, macrophage infiltration, and elevated collagen, alongside upregulated inflammatory factors (e.g., ICAM-1, MCP-1, TNFα).
• Significant metabonomic shifts occurred across multiple matrices, involving cholesterol homeostasis, amino acid/protein biosynthesis, gut microbiota, and vitamin B3 metabolism.
• WD promoted oxidative stress (elevated urinary allantoin, decreased hepatic PUFA/MUFA ratio) and down-regulated SCD1.
• Diet reversal partially alleviated metabolic changes and atherosclerosis markers, but lesions and inflammation persisted.

Conclusions:

• Fatty acid and vitamin B3 metabolism, along with gut microbiota functions, are critical in atherosclerosis development.
• Integrated multi-matrix metabonomic analysis provides detailed biochemical insights into diet-induced atherosclerosis.
• This approach is effective for understanding the molecular mechanisms of cardiovascular diseases.