One of the most common disorders globally, nonalcoholic fatty liver disease (NAFLD) is a leading cause of death worldwide. Its progressive form, called “nonalcoholic steatohepatitis” (NASH), affects about 30% of all NAFLD patients, and can lead to cirrhosis and liver cancer. Despite many research efforts, we still do not understand the underlying mechanisms of NAFLD/NASH and, consequently, lack an effective treatment.
One thing we do know, however, is that it seems to be more frequent among men than women, especially premenopausal women. Why this is so is not entirely clear, but current evidence suggests that the sex hormone estrogen plays a protective role. On the other hand, the protein formyl peptide receptor 2 (FPR2) is known to play an important role in mediating inflammatory responses in multiple organs. However, no study so far has determined its role in the liver. Could FPR2 be involved in the sex-related differences regarding NAFLD prevalence and severity?
Addressing this question, a research team led by Professor Youngmi Jung of Pusan National University, Korea, recently conducted a study using mice model, shedding light on the role of FPR2 in NAFLD/NASH and its relationship to the observed sex-based differences. This work is among the very few studies on NAFLD that relies on sex-balanced animal experiments rather than the more common male-only designs. This paper was made available online on 31 January 2022 and was published in Volume 13, Issue 578, of the journal Nature Communications on 31 January 2022.
The researchers first found that Fpr2 was highly expressed in healthy livers of female mice. Furthermore, it was expressed differently in the livers of male and female mice that were fed a special NAFLD-inducing diet. Silencing the Fpr2 gene made the male and female mice equally vulnerable to NAFLD, suggesting that FPR2 has a protective effect on the liver.
Interestingly, the researchers also found that FPR2 production in the liver is mediated by estrogen. Males supplemented with external estrogen produced more Fpr2 and were more resistant to NAFLD, whereas females that had their ovaries removed exhibited reduced liver Fpr2 levels. “Taken together, our findings suggest that FPR2 is a potential therapeutic target for developing pharmacological agents to treat NAFLD/NASH,” says Prof. Jung. “In addition, our results could help in the development of gender-based therapies for NASH.”
This unprecedented discovery of the female-specific production of FPR2 in the liver and its role in providing resistance against NAFLD/NASH will hopefully pave the way not only for novel treatments but also a more comprehensive and sex-aware approach when doing science. In this regard, Prof. Jung remarks, “Our research highlights the pressing need for designing and developing better sex-balanced animal experiments, considering that the sex-specific expression of FPR2 in the liver had been completely overlooked in previous studies.”
Let us hope this marks the beginning of a deeper understanding of NAFLD/NASH and the first steps towards effective sex-based therapies.
Authors: Chanbin Lee1, Jieun Kim1, Jinsol Han1, Dayoung Oh1, Minju Kim1, Hayeong Jeong1, Tae-Jin Kim1,2, Sang-Woo Kim1,2, Jeong Nam Kim1,3, Young-Su Seo1,3, Ayako Suzuki4, Jae Ho Kim5 and Youngmi Jung1,2
1Department of Integrated Biological Science, College of Natural Science, Pusan National University
2Department of Biological Sciences, College of Natural Science, Pusan National University
3Department of Microbiology, College of Natural Science, Pusan National University
4Division of Gastroenterology and Hepatology, Duke University
5Department of Physiology, Pusan National University School of Medicine, Pusan National University
About Pusan National University
Pusan National University, located in Busan, South Korea, was founded in 1946, and is now the no. 1 national university of South Korea in research and educational competency. The multi-campus university also has other smaller campuses in Yangsan, Miryang, and Ami. The university prides itself on the principles of truth, freedom, and service, and has approximately 30,000 students, 1200 professors, and 750 faculty members. The university is composed of 14 colleges (schools) and one independent division, with 103 departments in all.
About the author
Prof. Youngmi Jung earned her Ph.D. in Molecular Cellular Biology at the University of Florida, College of Medicine. She worked as research associate from 2006 to 2008 and as assistant professor from 2008 to 2010 at the Division of Gastroenterology of Duke University College of Medicine. In 2010, she joined the faculty of the Department of Biological Sciences at Pusan National University, where she has been working as Professor since 2019. Her research is focused on the mechanisms underlying the progression of liver diseases, particularly the cellular response of liver progenitor and hepatic stellate cells, and the micro-environmental changes caused by disease. Through her research, she aims to develop therapeutic methods to prevent the progression to chronic liver disease by utilizing the knowledge of the transdifferentiation mechanisms of progenitor and hepatic stellate cells.
Method of Research
Subject of Research
Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis
Article Publication Date
The authors declare no competing interests.