Navigating the complexities of non-alcoholic fatty liver disease (NAFLD), which impacts nearly one in three people globally, requires a deep understanding of its underlying causes. This disease, often associated with modern lifestyle choices such as sedentary behavior and high-fat diets, is a growing public health concern. The key to developing effective treatments lies in unraveling its molecular roots. At the forefront of this exploration is the groundbreaking work of Professor Jung Weon Lee and his team. Their focus on a critical protein, TM4SF5, sheds light on its role in this intricate disease. Their study in iScience offers new hope in transforming our approach to managing and treating NAFLD and its more severe form, non-alcoholic steatohepatitis (NASH).
In their innovative study, Professor Jung Weon Lee and his team including Yangie Pinanga, Eun-Ae Shin, Haesong Lee, Kyung-Hee Pyo, Ji Eon Kim, Eun Hae Lee, Wonsik Kim, Soyeon Kim in collaboration with Professors Han Ah Lee and Hwi Young Kim from Ewha Womans University, have revealed essential insights into the increasingly common issue of non-alcoholic fatty liver disease (NAFLD). Their work, published in iScience, centers on a membrane protein named TM4SF5, showing its crucial role in the development of NAFLD and its more severe form, non-alcoholic steatohepatitis (NASH).
The first author Yangie Pinanga, who has just depended her doctoral dissertation said “it was unexpected for the hepatocyte-TM4SF5-overexpressing mice consumed more food during day time when ther are supposed to be sleepy”. Professor Lee also explained the heart of their research, stating, “The presence of TM4SF5 in liver cells can lead to unhealthy changes in the liver due to abnormal eating habits, increased levels of the appetite-stimulating hormone apelin, and variations in SPP-1/OPN levels, even over short periods of regular or high-fat diets.” This insight underlines the significant impact of TM4SF5 on liver health, extending beyond simple dietary factors.
The team used a unique approach, involving specially modified mice, to investigate the effects of TM4SF5. These mice were altered to either have an excess or a complete absence of the TM4SF5 protein in their liver cells. This design allowed for an in-depth comparison of its impacts under different eating conditions. The researchers closely monitored the mice’s eating patterns in relation to their active and rest periods, gaining insight into abnormal eating behaviors connected to TM4SF5. They also performed detailed examinations of the liver tissues and blood samples, focusing on liver health indicators and hormones that influence appetite and metabolism during earlier stages of NAFLD features.
Professor Lee further elaborated on their findings, “Mice with increased levels of TM4SF5 showed unusual eating patterns, especially eating more during their usual rest periods. This unusual behavior was linked with higher levels of the TM4SF5 expression and apelin hormone.” This discovery is vital in connecting TM4SF5 to the development of chronic liver diseases like NASH.
The study also included human subjects, with analyses of samples from NAFLD patients. Professor Lee discussed the human health implications, noting, “The level of apelin in the blood appeared to rise in line with the level of TM4SF5 in the liver, body mass index (BMI), or the severity of NAFLD, although our findings were not conclusive due to the small number of samples.” This observation suggests a possible relationship between TM4SF5, apelin levels, BMI, and the progression of NAFLD.
In conclusion, Professor Lee’s research provides essential insights into the role of TM4SF5 in causing NAFLD and NASH through abnormal eating behaviors and hormonal changes. These pioneering findings open up new possibilities for treatment, potentially changing the way we approach liver diseases influenced by dietary habits, in addition to anti-TM4SF5 strategy.
Pinanga YD, Lee HA, Shin EA, Lee H, Pyo KH, Kim JE, Lee EH, Kim W, Kim S, Kim HY, Lee JW. TM4SF5-mediated abnormal food-intake behavior and apelin expression facilitate non-alcoholic fatty liver disease features. iScience. 2023 Aug 14;26(9):107625. DOI: https://doi.org/10.1016/j.isci.2023.107625
About the Authors
Dr. Jung Weon Lee is a professor at Dept. of Pharmacy, College of Pharmacy, Seoul National University (SNU), Republic of Korea. He earned a Ph.D. degree in pharmacology, University of North Carolina at Chapel Hill, NC, USA in 2000. He had a postdoc period at Memorial Sloan-Kettering Cancer Center, New York, NY, USA. In 2001, he came back to Korea, as an assistant professor at School of Medicine, SNU, Korea. In 2009, he moved to Dept. of Pharmacy, SNU and is now a full professor. His research has been mostly focused on how cellular functions including morphological changes and diverse functions could occur at the molecular levels especially in contexts under controls or influence of a tetraspanin TM4SF5 protein using in vitro cell and in vivo animal models together with possible clinical samples. As a membrane protein that is induced by inflammatory modulators in pathological situations, TM4SF5 forms a massive protein-protein complex called as TM4SF5-enriched microdomain (T5ERM) for the role as a membranous signaling hub. TM4SF5-mediated effects on the cellular functions can lead to development of nonalcoholic and chronic liver diseases. Therefore, he has certainly explored also to develop anti-TM4SF5 reagents (such as small molecules and therapeutic monoclonal antibody) to block TM4SF5-mediated liver disease including nonalcoholic steatohepatitis, fibrosis, and cancers. Theses days, his research team has a focus on exploring how TM4SF5 can function as an immune checkpoint and whether anti-TM4SF5 reagents can be new modalities for the purposes of immune therapy against chronic liver diseases (Orcid: https://orcid.org/0000-0003-2722-8200; Lab homepage: http://jwl.snu.ac.kr/).