The liver is a central organ of metabolism and detoxification. It plays a major role in the adaptation to the environment, especially food. Its ability to adapt to nutrient supply is based on the activation of different metabolic pathways (series of biochemical reactions) in main liver cells called hepatocytes. When sugar (glucose) is lacking, for example during fasting, the hepatocytes produce a new energy source from lipids, called ketone bodies. This fasting can be voluntary or secondary to an illness, such as infectious diseases. Ketone bodies represent an alternative and essential source of energy to compensate for the lack of glucose, especially for the brain and the heart. Several proteins, called transcription factors, cooperate to regulate genome expression in hepatocytes in order to maintain this energy balance in the body.
Liver activity shows differences between men and women, known as sexual dimorphism. Moreover, the sensitivity to metabolic diseases such as non-alcoholic fatty liver diseases (NAFLD) which represent a global public health issue is very dependent on gender. In the early stages of these diseases, hepatocytes accumulate abnormally high levels of lipids, which can promote progression to the severe stages such as hepatitis, cirrhosis, cancer. The work of the team led by Hervé Guillou and Nicolas Loiseau at Toxalim is interested in the dietary and environmental factors that influence metabolism and its role in liver diseases.
Dialogue between adipose tissue and liver: a mechanism identified
The transcription factor "Peroxisome Proliferator Activated Receptor" or PPARα, is an essential player in hepatocyte metabolism where it controls the expression of hundreds of genes. The team’s recent work indicates that it plays a central role in interactions between adipose tissue* and liver, brought into play during metabolic stress. This receptor is located in the hepatocyte's nucleus and regulates the expression of genes encoding limiting enzymes in the degradation of lipids from adipose tissue (adipocyte lipolysis) and in the synthesis of ketone bodies.
« Nous avons montré, en collaboration avec plusieurs équipes dont une équipe autrichienne de l’Université de Graz, que la lipolyse du tissu adipeux a une forte influence sur l’expression hépatique du génome, partage Anne Fougerat, chercheuse au laboratoire Toxalim. Une part importante de ces effets est contrôlée par le récepteur PPARα. La lipolyse adipocytaire est un signal déterminant pour l’expression de ces gènes nécessaires au contrôle de la dégradation des acides gras et à la production de corps cétoniques. L’ensemble de ce travail positionne le récepteur hépatocytaire PPARα à l’interface du dialogue métabolique entre le tissu adipeux et le foie. »
A role in metabolic liver diseases and sexual dimorphism
Scientists from Toxalim, Metabolic and Cardiovascular Research Institute (I2MC) and Toulouse University Hospital Center also analyzed hepatic regulators of adaptation to diets favoring the onset of liver diseases, in both sexes. Among the factors involved in this sexual dimorphism, researchers proved that PPARα receptor is one of the determinants of sex-related liver differences in mice. This is also the case in male and female patients with chronic non-alcoholic liver disease.
"This research identifies the transcription factor PPARα as a sex-specific regulator of liver function. This may play a role in metabolic and infectious diseases. But it is not the only factor contributing to liver sexual dimorphism. This is currently the subject of research programs in collaboration with Professor Pierre Gourdy's team at I2MC, thanks to the French National Research Agency (ANR) and the Fondation pour la Recherche Médicale support" emphasizes Hervé Guillou
Because PPARα is a target of many drugs in development and also of environmental contaminants (endocrine and metabolic disruptors), these findings illustrate the importance of considering metabolic dialogues between organs and gender specificities in health and medicine.
*Adipose tissue: tissue containing adipocytes, cells specialized in fat storage
Fougerat et al. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity. Cell Rep. 2022 Jun 7;39(10):110910. doi: 10.1016/j.celrep.2022.110910
Smati et al. Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Gut. 2022 Apr;71(4):807-821. doi: 10.1136/gutjnl-2020-323323