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Post-translational modifications, a key process in CD36 function: lessons from the spontaneously hypertensive rat
Benjamin Lauzier1, Clémence Merlen, Fanny Vaillant
1Montreal Heart Institute, Université de Montréal, Montreal, Quebec H1T 1C8, Canada.
Insights
Altered CD36 protein modifications in spontaneously hypertensive rats impair cardiac long chain fatty acid utilization before heart enlargement. This impacts heart disease research and therapeutic strategies.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- CD36 is crucial for cardiac long chain fatty acid (LCFA) metabolism and heart disease development.
- The functional consequences of genetic variations in CD36, particularly in disease models, are not fully understood.
Purpose of the Study:
- To investigate if defective CD36 post-translational modifications (PTMs) cause reduced cardiac LCFA utilization in spontaneously hypertensive rats (SHR) before the onset of cardiac hypertrophy.
- To explore the role of specific CD36 PTMs in regulating its membrane localization and function in LCFA metabolism.
Main Methods:
- Ex vivo heart perfusion using (13)C-labeled substrates in 7-week-old SHR and control rats.
- Biochemical techniques to assess protein levels, distribution, PTMs (N-glycosylation, O-linked-β-N-acetylglucosamine), and malonyl-CoA levels.
Main Results:
- SHR hearts showed significantly reduced LCFA contribution to β-oxidation (-40%) and altered triglyceride levels (+2.8 folds) compared to controls.
- These metabolic changes were not linked to transcriptional alterations or malonyl-CoA levels.
- SHR hearts exhibited decreased membrane-associated CD36 protein levels and altered N-glycosylation, with O-linked-β-N-acetylglucosamine being critical for CD36 membrane recruitment and LCFA utilization.
Conclusions:
- Defective CD36 post-translational modifications, specifically N-glycosylation, impair cardiac LCFA metabolism in SHR prior to hypertrophy.
- O-linked-β-N-acetylglucosamine is essential for CD36's membrane localization and function in cardiac LCFA uptake.
- These findings provide insights into CD36's role in heart disease pathogenesis and suggest potential therapeutic targets.
Abstract:
CD36, a multifunctional protein, is involved in cardiac long chain fatty acid (LCFA) metabolism and in the etiology of heart diseases, yet the functional impact of Cd36 gene variants remains unclear. In 7-week-old spontaneously hypertensive rats (SHR), which, like humans, carry numerous mutations in Cd36, we tested the hypothesis that their restricted cardiac LCFA utilization occurs prior to hypertrophy due to defective CD36 post-translational modifications (PTM), as assessed by ex vivo perfusion of (13)C-labeled substrates and biochemical techniques. Compared to their controls, SHR hearts displayed a lower (i) contribution of LCFA to β-oxidation (-40%) and triglycerides (+2.8 folds), which was not explained by transcriptional changes or malonyl-CoA level, a recognized β-oxidation inhibitor, and (ii) membrane-associated CD36 protein level, but unchanged distribution. Other results demonstrate alterations in CD36 PTM in SHR hearts, specifically by N-glycosylation, and the importance of O-linked-β-N-acetylglucosamine for its membrane recruitment and role in LCFA use in the heart.
