Research reveals the mechanism by which estrogen protects against fatty liver

New research from Karolinska Institute in Sweden revealed the protective role of estrogen against MASLD, a fatty liver disease that has surged amidst the ongoing obesity epidemic.

The findings, published in the Journal Molecular Systems Biology, showed how a new drug under development could become a future treatment for fatty liver disease and liver cancer.

The global obesity crisis has led to a sharp rise in fatty liver disease, where excess fat is stored in liver cells instead of fat cells. MASLD - metabolic dysfunction-associated steatotic liver disease- affects up to one in three adults. While MASLD can progress to severe conditions like cirrhosis and liver cancer, it majorly affects men.

“Women have a natural protection until menopause due to the female sex hormone oestrogen,” explained Claudia Kutter, senior researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska instituteand lead author of the study.

By genetically analyzing mice of both genders subjected to a high-fat diet, along with some male mice receiving estrogen, researchers pinpointed a crucial protein in fatty liver development. The protein, TEAD1, was discovered to regulate fat absorption in liver cells overall. Inhibiting TEAD1 shielded liver cells from detrimental fat buildup. Mice treated with estrogen exhibited reduced TEAD1 activity and less fat accumulation in the liver. Subsequent experiments blocking TEAD1 in human liver cells yielded similar outcomes.

“Since the activity of TEAD proteins is elevated in cancer, blocking TEAD at an early stage can also be positive from a cancer point of view,” said Kutter. “Patients suffering from liver cancer are currently diagnosed very late. If the patient is given this drug early in the process to protect against fatty liver, it can hopefully also prevent the development of liver cancer.”

“We want to focus on how to find the disease earlier and identifying new treatment targets. Different approaches may be needed for different patients depending on their gender and hormonal status.” concluded Kutter.

Reference: Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, and Claudia Kutter; Journal: Molecular Systems Biology; DOI: 10.1038/s44320-024-00024-x