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HNF4α: The Metabolic Mastermind in Sepsis
Sepsis, a huge unmet medical need
Sepsis is a life-threatening condition caused by an extreme response of the body to an infection. Under normal conditions, when people get an infection, the immune system can easily fight it. However during sepsis, the immune system goes into overdrive and starts attacking not only the infection but also the body itself. This overwhelming response often results in organ failure, severe metabolic changes in the liver and can even turn lethal if it progresses into septic shock. Sepsis is responsible for millions of deaths each year and is therefore recognized as a global health priority by the World Health Organization.
Over the past three decades, many clinical trials aiming to deal with sepsis have failed. But, the research group of Prof. Dr. Claude Libert (VIB-Ghent University in Belgium) has now identified a critical role for the transcription factor HNF4α in the liver. Transcription factors are proteins which help to activate or block the expression of certain genes and therefore influence how the body reacts to sepsis. This might improve the survival rate of sepsis patients when HNF4α is activated or stimulated, possibly paving the way for new therapeutic strategies for sepsis.
Why HNF4α matters in sepsis
Sepsis patients are often unable to eat, but require more energy to fight the infection. Under normal conditions, glucose will be produced and fat tissue and muscles will be broken down to provide new substrates such as free fatty acids that can be converted into new energy sources. However during sepsis, the function of several transcription factors is compromised. One important transcription factor is PPARα which is essential for fat metabolism and energy production in the liver. The aim of this research project was to understand how PPARα function in the liver is affected in septic conditions.
In the study, recently published in EMBO Molecular Medicine, the lab of Prof. Dr. Claude Libert has identified HNF4α as a metabolic mastermind during sepsis. Furthermore, the team has shown that HNF4α has a direct impact on how PPARα is functioning during sepsis. HNF4α is found in the liver, where it plays an essential role in liver development and in the differentiation of liver cells. Furthermore, HNF4α regulates the expression of genes involved in fat metabolism and glucose production and therefore has a big impact on liver metabolism. During sepsis, HNF4α is no longer capable of binding to the DNA and is thus no longer able to regulate liver metabolism in a proper manner. The downstream effects of HNF4α loss of function has a big impact on PPARα biology during sepsis. Normally PPARα is responsible for the conversion of free fatty acids into ketone bodies in the liver which can be used as a new energy source by the heart and brain. However, due to HNF4α dysfunction and thus PPARα dysfunction during sepsis, free fatty acids will accumulate in the liver and cause toxicity for the body.
HNF4α depletion: a silent killer
Depletion of HNF4α in liver cells worsens the outcome of sepsis. The study showed that the survival rate is reduced, associated with more severe accumulation of fat in the liver, and more severe organ damage. Furthermore, the absence of HNF4α is also linked with an inappropriate acute phase response. This is the body’s alarming system present in the liver when it detects an injury or infection. The liver will release special proteins into the blood to reduce inflammation, protect tissues and start the healing process. However, when HNF4α loses its function during sepsis, the liver is not able to produce enough of these special proteins. These insights provide crucial information of why certain sepsis patients struggle to recover, highlighting the importance of maintaining a proper liver function during infection.
A new therapeutic target
By activating HNF4α, we may be able to trigger a beneficial cascade effect that helps counteract sepsis and save the lives of patients. During this study, the authors discovered the therapeutic potential of a compound that is able to improve the function of HNF4α during sepsis. This compound promotes the survival rate during sepsis by restoring HNF4α function and reduces fat accumulation in the liver. Furthermore, this compound improves the hepatic alarming system in sepsis.
Now that the role of HNF4α has been identified, it might be of great interest to further explore this in clinical trials. Targeting this transcription factor offers a new hope in the treatment of sepsis, a condition that still claims millions of lives each year. Furthermore, HNF4α loss of function is also associated with several other metabolic diseases, such as alcoholic liver disease, diabetes, and liver fibrosis and cirrhosis. Therefore, HNF4α might also be a therapeutic target in these diseases. With this research, the team has solved a piece of the puzzle which might lead to new therapeutics for sepsis patients and patients with metabolic diseases.
Written by Tineke Vanderhaeghen
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