Low testosterone levels may significantly increase the risk of developing severe fatty liver disease when combined with a diet high in fructose, according to new research from Osaka Metropolitan University. The study, published in the American Journal of Physiology-Endocrinology and Metabolism, provides a detailed look at how hormonal changes and dietary habits interact to damage liver health.
Metabolic dysfunction-associated steatotic liver disease, or MASLD, affects approximately 40% of adult men globally. The condition begins with fatty liver, where excess fat builds up in the liver cells. While obesity, type 2 diabetes, and low testosterone are known risk factors, scientists have struggled to understand how these elements work together to accelerate the disease.
Combined Effects on Liver Health
Researchers led by graduate student Hiroki Takahashi and Associate Professor Naoki Harada designed an experiment to isolate the effects of testosterone and fructose. They used male mice divided into six groups. Some mice underwent castration to lower testosterone, while others had sham operations. The groups were then fed either a control diet or a high-fructose diet. Some high-fructose groups also received antibiotics to alter their gut bacteria.
The results showed that mice with low testosterone levels developed heavier livers when they consumed fructose. This effect was less pronounced in mice that also received antibiotics, suggesting that gut bacteria play a critical role in the process. When examined individually, low testosterone and high fructose intake caused only modest changes in liver triglyceride levels. However, when combined, the two factors led to a significant increase in fat accumulation.
The team analyzed liver cells, blood plasma, and samples of gut bacteria to understand the underlying mechanisms. They found that the combination of low testosterone and fructose altered liver gene activity and increased levels of pyruvate in the cecum, a part of the large intestine. Pyruvate is a compound involved in energy metabolism.
Gut Microbiome and Pyruvate
The study highlights the importance of the gut microbiome in liver health. Changes in gut bacteria appeared to increase intestinal pyruvate levels. Laboratory experiments using mouse-derived primary hepatocytes, or liver cells, revealed that pyruvate acts synergistically with fructose to promote neutral lipid accumulation in those cells.
“Upon examining this mechanism, we found that changes in the gut microbiota led to increased levels of pyruvate within the intestine,” Takahashi explained. “Furthermore, experiments using mouse-derived primary hepatocytes revealed that pyruvate acts synergistically with fructose to promote neutral lipid accumulation in hepatocytes.”
This finding suggests that the interaction between testosterone, dietary fructose, and gut bacteria creates a specific pathway that worsens fatty liver disease. The gut microbiome appears to be a key mediator in this process, converting dietary inputs into compounds that directly harm liver cells.
Professor Harada noted that these insights could lead to new preventive and therapeutic strategies. “Going forward, we hope to clarify the mechanism by which pyruvate promotes triglyceride accumulation to pioneer the development of therapeutic drugs and establishment of preventive methods through dietary interventions,” he added.
While the study was conducted on mice and isolated liver cells, it offers a clearer picture of how hormonal and dietary factors interact. The findings suggest that targeting the processes through which pyruvate contributes to fat accumulation could be a promising avenue for treating fatty liver disease. The research underscores the need to consider both hormonal health and diet when addressing metabolic liver conditions.
Source: ScienceDaily
