Home Medizin Eine proteinreiche Ernährung und ein erhöhter Spiegel der Aminosäure Leucin können zur Bildung von Plaque in den Arterien beitragen

Eine proteinreiche Ernährung und ein erhöhter Spiegel der Aminosäure Leucin können zur Bildung von Plaque in den Arterien beitragen

von NFI Redaktion

A recent study published in Nature Metabolism conducted clinical experiments on murine animals and humans to evaluate the effects of high protein intake on the amino acid-mTOR autophagy signaling pathway. They also examined the dose-response relationship, downstream effects, and amino acid specificity of mTORC1 activation.

Study: Identification of a leucine-mediated threshold effect controlling mTOR signaling of macrophages and cardiovascular risk.  Image Source: Crevis/Shutterstock.com
Study: Identification of a leucine-mediated threshold effect controlling mTOR signaling of macrophages and cardiovascular risk. Image Source: Crevis/Shutterstock.com

Background

Animal studies have shown that high protein intake in Western countries is associated with cardiovascular disease. Protein-rich diets promote atherogenesis through amino acid-mediated mTORC1 signaling and affect autophagy and mitophagy in macrophages. The specific joint processes underlying this activation are still unknown, although the authors speculate that the stimulating effect could be related to specific „pathogenic“ amino acids.

About the Study

In the current study, researchers conducted two clinical experiments to investigate the dose-response relationship between dietary protein intake and amino acid specificity of the amino acid-mTOR autophagy signaling pathway in human monocytes or macrophages.

The first experiment examined extreme protein consumption by investigating the influence of liquid meals with a protein content of 50% or 10% on the activation of the mTORC1 signaling pathway in monocytes. The second experiment used a more realistic setting and evaluated these results in subjects receiving standard protein meals or mixed meals with higher protein (15% kilocalories vs. 22% kilocalories). The study analyzed monocytes expressing the differentiation cluster 14 (CD14+) but not CD16, as they represent most monocytes in circulation and are most likely to develop into atherosclerotic macrophages.

The team performed flow cytometry and monocyte isolation from platelets. They used Western blot, fluorescence-activated cell sorting (FACS), and immunofluorescence to investigate the influence of meals with different protein content on serological amino acid levels, mTORC1 signaling in monocytes, and downstream consequences.

The team examined 14 overweight individuals [based on body mass index (BMI)] twice after a 12-hour overnight fast. The participants consumed low-protein and very high-protein meals. The researchers used cultured macrophages from human monocytes to investigate macrophage-specific mTORC1 response to amino acids and evaluate dosage effects.

They measured amino acid concentrations in plasma and macrophages using gas chromatography-mass spectrometry and quantified arginine levels in plasma using liquid chromatography-mass spectrometry. They determined the size of atherosclerotic lesions using Oil Red O staining of aortic root slices.

The researchers investigated whether leucine-dependent mTORC1 activation occurred in vivo in mice and cultured murine macrophages. ApoE knockout mice received six meals over an eight-week period, including a Western diet with moderate protein content, a Western diet with high protein content, a Western diet with moderate protein content with leucine and amino acids, more amino acids, and a nitrogen-adjusted version of moderate protein plus amino acids.

They investigated whether serum amino acids were present in C57BL/6J mice weaned at three weeks of age. In vivo After eight weeks, studies related to atherosclerosis began with male mice of the respective genotype receiving different diets.

Results

The study identified leucine as the primary activator of mTOR signaling in macrophages and showed a threshold effect of high protein intake and circulating leucine on monocytes or macrophages. Only protein above 25 g per meal activates mTOR and has functional consequences. Protein intake above 22% of the daily energy requirement triggers the harmful amino acid-mTORC1 autophagy signaling pathway in human monocytes and macrophages, causing atherosclerosis in male mice. The study revealed a strong correlation between high protein consumption and the risk of atherosclerotic cardiovascular disease, indicating the potential for dietary guidance and treatment measures.

The total amino acid content in plasma increased after consuming the high-protein liquid meal but not after drinking the low-protein meal. During the three-hour postprandial interval, consumption of the very high protein level enhanced mTORC1 signaling and gradually reduced the intensity of the LC3 signal, indicating mTORC1-mediated suppression of autophagy. Western blot analysis showed a robust dose-dependent effect of leucine-mediated mTORC1 activation in HMDMs, assessed by phosphorylation of ribosomal protein S6 and ribosomal protein S6 kinase (p-S6K).

The team also found a dose-dependent threshold effect for the colocalization of mTOR-LAMP2, suppression of autophagy (reduced LC3 puncta formation), and mitophagy (reduced colocalization of the mitochondrial marker COXIV with the autophagosomal marker LC3). They observed a significantly higher level of four amino acids (Leu, Ile, Val, and Thr) in mice after a protein probe compared to the control probe.

Leucine was the most effective mTORC1 activator, with 1.6 g of protein per kg from the gavage resulting in higher mTORC1 activation than 0.8 g of protein per kg from the gavage. The study revealed that increased leucine content in the diet is both necessary and sufficient to achieve the pro-atherogenic effect of a high-protein diet in vivo.

The study’s findings indicated that high protein consumption, especially through increased leucine levels in plasma, could suppress mTORC1-mediated autophagy and atherogenesis in monocytes and macrophages, with significant implications for clinical and public health.

While higher protein consumption than the recommended amount of 0.8 grams/kg/day is considered safe, the study recommends caution and further clinical trials. Leucine was the primary amino acid responsible for mTOR activation in macrophages, and increased protein consumption had a threshold effect on the harmful signaling pathway.

A comprehensive examination is necessary to determine the exact threshold between the benefits of dietary proteins and the negative impacts on health.

Journal Reference:

  • Zhang, X., Kapoor, D., Jeong, SJ. et al. Identification of a leucine-mediated threshold effect controlling mTOR signaling of macrophages and cardiovascular risk. Nat Metab 6, 359–377 (2024). doi: https://doi.org/10.1038/s42255-024-00984-2

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