Research Report on the Relationship Between High Protein Diet and Liver Fat Synthesis

Background and Significance

Globally, the prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is gradually increasing, becoming a common issue among people with obesity and insulin resistance. The pathological development of this disease includes fatty liver, hepatitis, fibrosis, and ultimately cirrhosis. Although the formation of fatty liver is closely related to de novo lipogenesis (DNL), the carbon source of more than half of the fatty acids (FAs) in the liver remains unclear. Traditionally, carbohydrates are considered the primary carbon source for fat synthesis. However, some studies suggest that carbohydrates like glucose directly contribute very little to the synthesis of fatty acids, primarily being stored as glycogen.

This study, conducted by Yilie Liao of the Zhongshan Institute for Drug Innovation (ZIDD), Qishan Chen of the Guangzhou National Laboratory, and Lei Liu of Tsinghua University, was published in the November 5, 2024, issue of “Cell Metabolism”. Based on the latest National Health and Nutrition Examination Survey (NHANES) data, combined with various chemical, genetic, and dietary intervention experiments, the study reveals that a high-protein diet may be an important risk factor for MASLD, with amino acids being the main carbon source for liver fat synthesis. This study presents a unique perspective that amino acids are key nutritional sources for fat synthesis, providing new directions for nutritional interventions in MASLD.

Research Process and Methods

Data Analysis and Experimental Design

The study first used NHANES data to compare the association of protein, carbohydrate, and fat intake with the prevalence of MASLD. Results showed a positive correlation between protein intake and the occurrence of MASLD among obese populations, while carbohydrate and fat intake did not significantly increase the risk of the disease. Subsequently, the authors isolated primary hepatocytes from mice and used 13C isotope tracing experiments to compare the roles of glucose and glutamine in the tricarboxylic acid (TCA) cycle and fatty acid synthesis, confirming that amino acids are the main carbon providers for liver fat synthesis.

Relationship Between Protein Intake and MASLD

NHANES data analysis indicated that among groups with higher protein intake, the risk of MASLD increased significantly, especially among obese individuals and those over 60 years old. Further analysis suggested that the risk effect of a high-protein diet is similar to that of a high-fat diet, in stark contrast to the negative correlation with carbohydrate intake. This result suggests that high protein intake may influence liver fat accumulation through amino acid metabolic pathways.

Contribution of Amino Acids to the TCA Cycle

The liver is the primary site for amino acid metabolism. Transcriptomics analysis revealed that the expression of amino acid metabolic genes in the liver is significantly higher than that of glycolysis genes. In in vitro experiments, mouse primary hepatocytes showed a significantly higher rate of amino acid oxidation compared to glucose, with glucose seldomly used for the TCA cycle under normal conditions. To verify the contribution of amino acid metabolism to liver fat synthesis, researchers utilized 13C-glutamine as a tracer and found that glutamine not only provides a carbon source for the TCA cycle but also participates in fatty acid generation, especially under obesity conditions where its utilization significantly increases.

Amino Acids as Carbon Sources for Liver De Novo Lipogenesis

Further experiments demonstrated that amino acids enter the fat synthesis pathway via the export of citrate. Compared to glucose, the 13C labeling of amino acids in the fatty acid content of liver cells increased significantly. The study also found that even under normal culture conditions, the fat generation potential of glutamine and other amino acids far exceeded that of glucose. This suggests that amino acids might be the primary carbon contributors for DNL in the liver, rather than glucose as traditionally thought.

Dietary Intervention Experiments

To further confirm the role of amino acids in MASLD, the researchers randomly divided obese mice into standard protein and low-protein diet groups. The results showed that a low-protein diet significantly reduced liver fat accumulation and alleviated liver damage. Moreover, the expression of fat synthesis-related genes in the low-protein diet group generally decreased, while the expression of the FGF21 gene, related to amino acid deficiency, increased significantly. Protein restriction not only reduced weight gain but also inhibited the expression of liver fat metabolic genes, mechanistically supporting the potential pathogenic role of amino acids in MASLD.

Research Conclusions

This study systematically reveals for the first time the role of amino acids as the main carbon source for liver fat generation and finds that a high-protein diet may increase the risk of MASLD. This result subverts traditional views and suggests that protein intake amounts and quality must be considered in nutritional interventions for MASLD. Additionally, the study shows that dietary intervention to modulate amino acid metabolic pathways can effectively alleviate liver fat deposition, providing new insights for the prevention and treatment of MASLD.

Research Highlights

1. Risk of Protein Intake and MASLD: The study uses large-scale NHANES data to find that a high-protein diet is a significant risk factor for MASLD, challenging the dominant role of carbohydrates in fatty liver formation.
2. Amino Acids as Major Fat Synthesis Carbon Sources: In vivo and in vitro isotope tracing experiments confirm that amino acids surpass glucose as the primary carbon providers for liver de novo fat synthesis.
3. Potential of Dietary Intervention: A low-protein diet significantly reduces liver fat accumulation in obese mice and regulates the expression of related fat metabolic genes, offering a potential MASLD intervention strategy.

Research Value and Outlook

This study reveals the potential risk of a high-protein diet in MASLD and the importance of amino acids in fat synthesis, broadening understanding of liver fat metabolism, and suggesting the need to monitor protein intake amounts in dietary planning. Future studies should further verify the specific roles of different types of amino acids in MASLD pathology and explore the long-term effects of low-protein diets. Additionally, the study’s results provide a theoretical foundation for the development of MASLD treatment drugs targeting amino acid metabolism.