Birt-Hogg-Dubé Syndrome (BHD) is caused by mutations in the gene folliculin (FLCN). We have previously covered some of the roles FLCN plays within our cells that contributes to the manifestations seen in BHD (link to blogs). Most of the research done on FLCN has been focused on the role of FLCN in the kidneys or lungs as these are the tissues most relevant to BHD. However, FLCN is expressed in the majority of our tissues and so it may be important to understand the role FLCN plays in other parts of the body. A recent study by Paquette et al., has uncovered a surprising role for FLCN in the liver in the context of fatty liver disease progression.
Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and is associated with obesity, type 2 diabetes and dyslipidemia (unhealthy levels of fat in the blood e.g. high cholesterol). Around one third of patients will progress to non-alcoholic steatohepatitis (NASH), which is characterised by liver damage, persistent inflammation fibrosis (scarring) due to accumulation of lipids (fats) in the liver. Around one third of NASH cases will lead to liver cirrhosis and liver failure. There are no approved drugs to treat NASH or to slow its progression.
How does FLCN play a role in fatty liver disease?
As it is accumulation of lipids in the liver that drives damage, regulation of lipid levels is crucial to maintain a healthy liver. FLCN is a known regulator of a protein called AMPK (AMP-activated protein kinase), a master regulator of cellular energy metabolism. Importantly, AMPK controls the switch from the generation of fatty acids to their breakdown. Loss of FLCN leads to a chronic activation of AMPK, which could be beneficial in the context of fatty liver disease. To study the role of FLCN in the role of liver fibrosis progression, the authors of the study generated a mouse model that lacked FLCN specifically in the liver and examined fatty acid accumulation and liver damage.
Firstly, they fed a high-fat diet to the mice lacking FLCN in the liver, or control mice and found that the control mice gained significantly more weight. When they looked at the livers of these mice, they could also see a reduction in fat droplets in the mice lacking liver FLCN compared to control.
Secondly, they fed the same mice a specific diet that results in the onset of NASH-like symptoms such as liver fibrosis. Unlike the high fat diet in the first experiment, this diet-induced model of fibrosis does not lead to weight gain. Again, they saw significant reduction in fat accumulation in the livers lacking FLCN compared to control. They also saw reduced markers of liver fibrosis and inflammation in the absence of FLCN in the liver, demonstrating that a loss of FLCN protects against liver damage in this context.
This is the first time a protective role for FLCN has been demonstrated in the liver. The authors of the study also saw no harmful effect of FLCN deletion in the liver which means there is potential for FLCN to be targeted therapeutically for fatty liver disease. It may be possible to develop a drug that is able to inhibit FLCN in the liver and could represent a new treatment route for NASH and even obesity. However, extreme care would have to be taken so that the loss of FLCN is specific to the liver, and would not be able to result in any of the manifestations seen in BHD.
What does this mean for individuals with BHD?
This was not addressed in the current study and so it is currently unclear if there are any consequences for individuals with BHD. It would be extremely interesting to look at samples of the liver in BHD patients or to examine the prevalence of fatty liver diseases within the BHD community. However, it is important to remember that these studies were conducted in mice lacking FLCN in only the liver, and were fed particular diets to induce a model of liver fibrosis and disease and as such may not be reflective of what happens in an individual with BHD.