Women can count on a secret weapon – a protein – that protects their liver against the consequences of high-sugar and high-fat diets, found a group of researchers from the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute.
More specifically, the team, led by Jennifer Estall, Director of the IRCM Molecular Mechanisms of Diabetes research unit, identified a protective pathway that works through estrogen, which is why it favours females over males. The research was recently published in Gastroenterology.
A pathway that could help reduce diabetes risks
It is well known that women are less affected by metabolic disease, at least for a certain part of their life. Before reaching menopause, women are 1.5 to 2 times less likely to develop non-alcoholic fatty liver disease (NAFLD), a disease that is strongly associated with obesity and type 2 diabetes and worsened by high-fat and high-sugar diets. The IRCM team managed to identify a protein that could explain why young females are more protected.
Previous research had established that a protein named PGC1A, which helps regulate metabolism in fat and muscle, was present in lower levels in livers of patients with NAFLD. This observation intrigued researcher Jennifer Estall and her team. “We wanted to see whether there was a causal relationship between the presence of low PGC1A and NAFLD, or if it was purely coincidental,” explained Dr. Estall, who is also an Assistant Research Professor at Université de Montréal and an Adjunct Professor at McGill University.
In order to do so, the team observed mice that had lower PGC1A levels in their liver, giving them a high-fat and high-sugar diet to induce NAFLD. “Usually, when given these diets, males have much more fat accumulation and damage to their liver than females,” said Aurèle Besse-Patin, PhD student in Dr. Estall’s lab and first author of the article. “But this time, both sexes seemed to develop more comparable damage.”
It was as if, by reducing PGC1A levels, the IRCM team had blocked a mechanism that females particularly rely on. The group demonstrated that estrogen acts through PGC1A to protect the liver from the damaging effects of obesity. The fact that the mechanism is activated by estrogen might contribute to why women have increased risk of developing NAFLD after menopause when estrogen levels drop, but further studies will be required to confirm this hypothesis.
A great share of women may benefit from PGC1A, however the protection is not universal. Dr. Estall’s team showed that a gene variant found in approximately 50% of the population could lead to low levels of PGC1A. Therefore, women with this version of the gene might have higher risks of getting fatty liver disease than their peers, although Dr. Estall emphasizes that the variant itself does not cause NAFLD. “The increase in risk can only be calculated after considering a combination of other factors, such as dietary habits and physical activity,” she said.
Moreover, the study highlights the importance of including both male and female populations in biomedical research and to consider sex as a variable. Until a few years ago, studying both male and female populations was seen as merely doubling a study’s costs and duration, but the practice is gaining popularity in the research community and proves to be effective, including in Dr. Estall’s study. “Had we not included female mice and compared both sexes, our team would not have shown that in the liver, PGC1A is influenced by estrogen,” Dr. Estall concluded. “More importantly, we would have missed what could become a promising additional therapeutic target for the treatment of women with fatty liver disease.”
About the study
The research project was carried out at the IRCM Molecular Mechanisms of Diabetes research unit by Aurèle Besse-Patin, Mélissa Léveillé, Daniel Oropeza and Jennifer Estall. Annik Prat, from the IRCM Biochemical Neuroendocrinology research unit, and Bich N. Nguyen, from the Centre hospitalier de l’Université de Montréal, were also involved in the study. The research received financial support from the Canadian Liver Foundation, the Canadian Institutes of Health Research and the Fonds de recherche Québec – Santé. Aurèle Besse-Patin and Mélissa Léveillé each received a scholarship from the IRCM Foundation as well as a scholarship from Université de Montréal’s Faculté de médecine.
About the IRCM
Founded in 1967, the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute is a non-profit organization that conducts fundamental and clinical biomedical research in addition to training high-level young scientists. With its cutting-edge technology facilities, the institute brings together 33 research teams, which work in cancer, immunology, neuroscience, cardiovascular and metabolic diseases, systems biology and medicinal chemistry. The IRCM also operates a research clinic specialized in hypertension, cholesterol, diabetes and cystic fibrosis, as well as a research centre on rare and genetic diseases in adults. The IRCM is affiliated with the Université de Montréal and associated with McGill University. Its clinic is affiliated with the Centre hospitalier de l’Université de Montréal (CHUM). The IRCM is supported by the Ministère de l’Économie, de la Science et de l’Innovation (Quebec ministry of Economy, Science and Innovation).
Source:
Anne-Marie Beauregard, Communication Advisor
Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute
514 987-5555 | anne-marie.beauregard@ircm.qc.ca
