Professor Luca Valenti: Molecular genetic characteristics and clinical application of metabolic fatty liver disease (MAFLD)

Editor's note: Metabolism-related fatty liver disease (MAFLD) is the most common form of chronic liver disease in the world. It is the general name of a series of liver diseases including steatosis, nonalcoholic steatohepatitis, cirrhosis and eventually hepatocellular carcinoma. At present, it is known that MAFLD is a complex systemic metabolic disease affected by multiple factors such as heredity and behavior habits, and involved in multiple pathways. Lipid ectopic deposition and insulin resistance are recognized as two major causes, but the specific pathogenesis is still unclear. At the 32nd annual meeting of the Asia-Pacific Association for Liver Research (APASL), this journal had the honor to interview Professor Luca Valenti of the University of Milan, Italy, and shared the molecular genetic characteristics and clinical application of MAFLD.

IH：Could you introduce some significant features of metabolic fatty liver disease (MAFLD) in epigenomics and genomics?

Dr Valenti: First of all, thank you for your invitation. The topic of my talk was the genomics and epigenomics of metabolic associated fatty liver disease, because this is the most prevalent liver disease right now worldwide. This condition has a strong heritable component, meaning that a large fraction of the risk of developing fatty liver disease is explained by inherited factors. This means that genetic factors or epigenetic factors are mitigated through the sequence of DNA. During the presentation, I reviewed the major findings, especially related to the genetic factors leading to a predisposition for fatty liver disease, which we started working on about 15 years ago with the identification of the major genetic factor for this condition, the PNPLA3 gene, which led to subsequent discoveries related to the genetic predisposition of this condition. 

IH：In general, what clinical characteristics of patients with MAFLD are closely related to their clinical outcomes?

Dr Valenti: The clinical factors that are most strongly associated with the risk of liver-related outcomes (meaning the development of cirrhosis and its complications, and particularly hepatocellular carcinoma) are, besides the age of the patient (because the risk increases with aging), in women, are being post-menopausal, and the major one is the severity of the metabolic alterations underlying the disease, meaning the severity of insulin resistance, and in particular, the development of diabetes, which is the major risk factor for this condition. Other risk factors are represented by excess alcohol intake, but the risk of complications are strongly dependent on the stage of liver disease, meaning the severity of liver fibrosis, which can be diagnosed histologically or using non-invasive biomarkers, such as the FIB-4 index or the use of physical methodologies like the measurement of liver stiffness by transient elastography.

IH：What epigenomic and genomic characteristics of MAFLD patients can be used to predict the outcomes of patients? Is there a potential target for the development of therapeutic drugs for MAFLD?

Dr Valenti: We have found in recent years that about half of the risk of developing severe liver disease in individuals with metabolic risk factors (obesity and diabetes) is explained by genetics, meaning there is a genetic predisposition for developing liver disease in genes regulating lipid metabolism and the compartmentalization of fat into the liver. These factors are inherited at conception, so they are present at birth and can be determined at that time. So this can be assessed in very young individuals (children and adolescents) to predict the risk of developing severe complications due to liver disease through their lifetime. One possibility is to concentrate our approach on changing lifestyle and increasing physical activity and a healthier diet in young individuals to prevent complications of liver disease. Or in older adults already with some degree of liver disease to predict, even before cirrhosis and a higher risk for liver cancer occurs, to guide stricter surveillance for the complications of liver disease. In the future, what I showed in my presentation is that we have identified through these genetic variants some new therapeutic targets. There are studies showing that we can more-or-less cure the mutation that predisposes to liver disease. We can detect the presence of these mutations, and in patients carrying these mutations, we can use drugs that target the liver that can, for example, basically turn off the bad genes. There are already clinical studies using this approach with people targeting the PNPLA3 mutation predisposing to fatty liver disease, and we will know next year whether or not that is effective.

We can use these genetic factors to predict the risk of disease on one hand, and on the other hand, we can use the presence of these genetic factors to identify targets for therapy. One possibility I was referring to before is to silence or turn off the bad genes that predispose to disease. Another possibility is to even mimic the effects of a protective mutation that protects against fatty liver disease. For example, there is a gene that metabolizes steroids in the liver, and some people have a variant that does not work very well but that protects against fatty liver disease, so our research is trying to mimic the effect of that mutation by using drugs that turn off this gene. There are promising studies that show this might be effective at decreasing the development of MAFLD. Again, we will see, but I think the results are very promising, and may open up a completely new approach for the treatment of the disease.