Italian researchers reveal the identikit of the most aggressive variant of fatty liver, in technical jargon hepatic steatosis, which affects women in menopause. The study – signed by Policlinico and the State University of Milan, published in ‘Nature Medicine’ – used sequencing and genetic editing techniques combined with simulations with organoids, to discover the interaction between a genetic variant and the female sex, responsible of the onset of fatty liver in women. The authors consider the work a step forward on the road to precision medicine.
Hepatic steatosis (Steatotic Liver Disease or Sld) – they recall from UniMi and Irccs of via Sforza – is the main liver disease that affects a third of the world’s population and is constantly increasing, especially among women. It is caused by an accumulation of excess fat in the liver, which triggers a state of chronic inflammation in the liver. At the basis of Sld there is the interaction of various factors: incorrect lifestyles and diets, some pathologies including diabetes and obesity, hereditary predisposition, increased cholesterol and triglycerides, arterial hypertension and overweight. Complicating the picture is the ‘silentness’ of fatty liver, often suspected only after an occasional finding of altered blood tests (for example transaminases), as well as the fact that no therapies are yet available to counteract the progression of the disease towards advanced forms. Experts believe that in the next 10 years, SLD will become the leading cause of cirrhosis, transplantation and liver cancer, particularly in women. Although estrogens protect them during the fertile years, after menopause some suffer from a more serious form of the disease.
It is precisely to clarify this aspect that the Milanese scientists designed a study with the participation of various international centers, for a total of over 4 thousand SLD patients. Furthermore, a cohort of almost 5 thousand blood donors was studied, who are part of the cardiometabolic prevention programs of the Transfusion Medicine of the Milan Polyclinic, directed by Daniele Prati.
Thanks to modern laboratory techniques, such as next generation genetic sequencing, organoids and Crispr-Cas9 – a note details – it was possible to highlight a specific interaction between the female sex and the Pnpla3 p.I148M genetic variant in determining the onset and severity of Sld. Previous studies had already demonstrated the association of this mutation with an increased risk of cirrhosis and liver cancer, due to the production of an altered protein that is unable to eliminate triglycerides from hepatocytes.
However, the researchers observed that the mutated Pnpla3 protein is present mainly in the livers of women, compared to those of men. A difference to be attributed to the presence of a specific DNA sequence of this gene, to which estrogen receptors bind, which induce the expression of Pnpla3 even in response to low hormone levels. With the hormonal and metabolic changes linked to menopause, therefore, the risk of Sld increases in women carriers of the p.I148M variant which causes accumulation in the lipid droplets of liver cells, leading to inflammation and the formation of scar tissue (hepatic fibrosis).
“An important result – we read in the note – obtained from the great team work of many teams at the Polyclinic, from Transfusion Medicine to Pathological Anatomy, up to Metabolic Medicine, Gastroenterology and Hepatology, General Surgery – Liver Transplants, who collaborated in various capacities in the development of the research”. Says Alessandro Cherubini, transfusion medicine researcher and first author of the article. “The study, in addition to defining a key molecular mechanism in the progression of Sld in women, suggests new therapeutic treatments that take into account both genetic variability and the patient’s clinical history. These new precision medicine approaches could prove particularly effective in women who develop steatosis especially after menopause.”
The research data were obtained through the study of hepatic cell lines and ‘mini-livers’ developed in the laboratory by researchers led by Luca Valenti, associate professor of Internal Medicine at the University of Milan and head of the Biological Resources Center of the Polyclinic, and confirmed by the analysis of the large population study in the UK Biobank.
“This publication – comments Valenti – underlines the importance of involving, together with large multicenter collaborations and biobanks capable of collecting the genetic data of large populations, blood donors in research projects on genetic and metabolic pathologies. The cohorts of donors, in addition to providing fundamental reference data for genetic studies, make it possible to monitor and define the subclinical phases of diseases, facilitating the design of targeted prevention and therapy programs”.