Relationship between fatty liver, DNA damage and liver cancer


Chantal Desdouets’ team at the Centre de Recherche des Cordeliers has just elucidated a new step in the chain reaction that leads to the aggravation of fatty liver disease or soda disease.

Romain Donné et al. show that the accumulation of fat in the liver induces DNA damage, which slows down and alters DNA replication, and provokes an inflammatory reaction that is known to promote the development of tumors.

These results, published in Developmental Cell, could lead to the development of innovative therapeutic strategies for obese patients in particular, and more generally for all patients with fatty liver disease.

©Developmental Cell

Non-Alcoholic Fatty Liver Disease (NAFLD), commonly called fatty liver disease or soda disease, has become a real pandemic in industrialized countries. This disease mainly affects overweight people and is associated with type II diabetes. Schematically, an excessive accumulation of adipose tissue in the abdominal cavity leads to a release of fat into the bloodstream, which is discharged into the liver. The hepatocytes, which are the cells essential to the major functions of this tissue, absorb this fat. Unfortunately, in about twenty percent of cases, this fat overload creates toxicity, cell death and inflammation. Over time, patients with this disease develop more serious problems such as fibrosis, cirrhosis and liver cancer, as they do with excessive alcohol consumption. Currently, the only way to manage the early symptoms of NAFLD is to make major lifestyle changes, which are often very difficult to implement and maintain. The prevalence of NAFLD will inexorably reach 35% of the population in the coming decades. Improving knowledge about this metabolic disorder has become a major public health issue.

Chantal Desdouets and her collaborators in the Proliferation, Stress and Hepatic Physiopathology team at the Centre de Recherche des Cordeliers have recently identified molecular factors involved in the aggravation of fatty liver disease.  Their work demonstrates that a hepatocyte overloaded with bad fats (saturated fats) shows genome alterations. The researchers compared the division cycle of these cells with that of healthy cells. They observed that in fatty hepatocytes, DNA replication (chromosome doubling) is slowed down compared to healthy cells, resulting in DNA breaks. A leakage of DNA is then observed in the cytoplasmic compartment of these cells. This DNA activates an inflammatory response recently identified as having a major role in the control of tumorigenesis, the cGAS-STING pathway. They also analyzed various biological parameters in a cohort of obese patients who developed fatty liver disease. They observed that this organ shows changes in the quantity of factors essential to DNA replication. The authors finally demonstrate in fatty hepatocyte cultures that the addition of replication factors identified as altered in patients induces a decrease in DNA damage and consequently a reduction in the inflammatory program mediated by the cGAS-STING pathway.

These novel results reveal a link between fat accumulation, DNA damage and activation of an inflammatory program involved in tumorigenesis processes. These results open important therapeutic perspectives for obese patients and for fatty liver disease in general.

Chantal Desdouets’ team is labelled “Equipe FRM”.

Reference :  Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD.  Donne R, et al. Dev Cell. 2022. PMID: 35768000