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Role of FGF21 in NAFLD-associated hepatic insulin resistance
Dr. François Jornayvaz, University of Geneva
Hjelt grant holder 2013
Dr. François Jornayvaz
University of Geneva
Dr. François Jornayvaz, MD, Service of Endocrinology, Diabetes, Hypertension and Nutrition, Geneva University Hospitals, received a subsidy for the project entitled “Role of FGF21 in NAFLD-associated hepatic insulin resistance”. Obesity leads to insulin resistance in the liver and other organs. Liver insulin resistance is associated with non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder. The project aims at evaluating the circulating protein fibroblast growth factor-21 (FGF21) on improvement of insulin action in the liver. The effects of FGF21 on various lipids in the liver of obese mice will be studied. The mechanism of action of FGF21 will also be elucidated in immortalized liver cells with special focus on the oxidation (degradation) of lipids by the mitochondria, the power generators of the cell. Finally, liver biopsies from healthy and obese subjects will be examined for the relationship between content of FGF21 and various lipid types. The project should validate the usefulness of FGF21 for the treatment of obesity and type 2 diabetes.
The Hjelt Foundation Interview with Dr. François Jornayvaz:
Obesity is rapidly rising worldwide and is associated with diseases such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. NAFLD is now the most prevalent chronic liver disease, affecting approximately 1 out of 4 individuals, and is strongly associated with hepatic insulin resistance.
Fibroblast growth factor 21 (FGF21) is an endocrine factor mainly acting in the liver. FGF21 improves insulin sensitivity in animal models of insulin resistance and is gaining interest as a therapeutic agent. However, its exact mechanisms of action, particularly on hepatic insulin resistance, remain largely unknown.
François Jornayvaz from Geneva University recieved 20 000 Euro from the Hjelt Foundation. The aim of his project is to study the mechanisms by which FGF21 improves hepatic insulin resistance in NAFLD. The main hypothesis is that FGF21 decreases hepatic lipid content, mostly lipid intermediates involved in the development of hepatic insulin resistance, i.e. diacylglycerol and ceramide. We also hypothesize that this decrease in hepatic lipid content might be secondary to an FGF21-mediated improvement in hepatic mitochondrial oxidative function.
This project will help understand the role of FGF21 in NAFLD-associated hepatic insulin resistance in vitro but also in vivo in mice and humans. The suggested experiments will also provide cellular mechanisms by which FGF21 improves NAFLD and insulin sensitivity when injected in a rodent model of insulin resistance, more specifically in, but not limited to the liver. This is highly relevant given the potential use of this endocrine factor as a therapeutic agent in the future in humans in the treatment of insulin resistant states such as NAFLD, obesity or type 2 diabetes. Given the high and ever increasing prevalence of these major health problems, and despite numerous treatments available, there is still a need to better understand their pathogenesis in order to develop targeted therapeutic molecules. If FGF21 is found to improve hepatic mitochondrial function, these studies might also open new perspectives in the field of mitochondrial related diseases such as Alzheimer’s disease and cardiovascular diseases.
This is a translational project, meaning that we will first use hepatic cell lines (from human liver cancer) and study the effect of FGF21 on these cells, notably on mitochondrial function. This is important, as mitochondria are involved in lipid oxidation. We will also study mice that have fatty livers secondary to dietary interventions. We will assess different lipid metabolites in these livers, mostly those associated with insulin resistance, which is a key step in the development of type 2 diabetes. We hope that FGF21 will ameliorate NAFLD and hepatic insulin resistance in these conditions. If true, this opens perspectives in humans in the treatment of NAFLD, but also for other diseases associated with insulin resistance, such as type 2 diabetes and obesity. Finally, we plan to set up a liver biopsies bank from patients with NAFLD, but also from healthy patients, in order to better understand how insulin resistance and type 2 diabetes develop in the presence of NAFLD.
What is your long term goal?
– As a physician, I am always patient-oriented in my research. Studies in cells and animals are necessary for some research aspects such as mechanisms comprehension, but my long-term goal is to better identify cellular targets that could be used in the treatment of type 2 diabetes in humans.
What is your personal driving force?
– Diabetes is a difficult disease. It is chronic and you have to think about it every day. Although lots of medications are available, we still miss efficient, safe and global molecules to better control diabetes. I therefore think that just prescribing drugs is not enough and I would like to contribute to a better understanding of this complex disease in order to find specific treatment targets. However, I also think that prevention is the key, i.e. notably avoiding obesity by eating a healthy diet and having regular physical activity. Unfortunately, type 2 diabetes is not only an environmental disease and has a genetic component. You cannot fight your genes and sometimes even if you do your best in term of lifestyle interventions to avoid diabetes, this will not be enough. By seeing all diabetes related complications in the clinic, I couldn’t just renew prescriptions or assist without power to the unfortunate fate of some patients. I therefore decided to be part of the scene and engaged into research. My patients are my best inspiration to develop and improve my research.
Sara Liedholm