February 9, 2023

Multiomics Characterization of Nonalcoholic Steatohepatitis in the BXD Mouse Genetic Reference Population

2nd Call, TPdF

Short Summary

NASH (non-alcoholic steatohepatitis) is an inflammatory liver disease driven by the abnormal accumulation of fat in the liver cells. NASH is associated with obesity and diabetes and its prevalence is increasing exponentially in the western societies. Despite conspicuous efforts, we still have limited understanding of the disease mechanisms and no drug available for the treatment of NASH. Both genetic and environmental (diet) factors influence the development of NASH. In this study, we will induce NASH in mice using a western diet (high in fat and sugar) at thermoneutrality (a situation much closer to the human condition). We will apply this protocol to a genetically heterogeneous mouse population that mimics the genetic diversity of the human population with the objective to find new drug targets and better mouse models of the disease.

Goals

We will induce NASH in a genetically heterogeneous mouse population to identify the mouse model that best reproduces the human disease. We will also characterize the genetic determinants of the disease in depth at the molecular level and establish a new signature set of genes and networks that characterize NASH/NAFLD in mice, with the goal to translate these findings into targeted human therapies.

Significance

Nonalcoholic fatty liver disease (NAFLD) is characterized by an abnormal accumulation of lipids in the hepatocytes and affects 25% of the world population. NAFLD can progress to NASH, liver fibrosis, cirrhosis and hepatocellular carcinoma. NASH is now the second indication for liver transplantation and will likely become the primary indication for liver transplantation by 2020. Despite the high prevalence, our understanding of the disease is still very limited and there is no therapy for the treatment of NASH. With this proposal we will: (1) Identify the mouse model that better reproduces the human disease, and will allow to test new drugs and drug targets; (2) identify a novel set of genes that characterize NASH/NAFLD in mice, with the goal to translate these findings to humans.

Background

Although several compounds are being tested for the treatment of NASH, none of these has so far lead to a significant improvement of the disease. Drug development for NASH has been hampered both by the still limited understanding of the disease mechanisms and by the lack of appropriate mouse models. The success of clinical trials would greatly benefit from the development of powerful preclinical models that reproduce faithfully the pathogenesis of the human disease. Most animal models of NASH are based on different types of diet (high-fat diet, high-fructose diet, etc.), and they are often only examined on a single genetic background. While these models can reproduce some aspects of the disease, they fail to faithfully reproduce the human condition.

Publications

Reynaud-Dulaurier R*, Benegiamo G*, Marrocco E, Al-Tannir R, Surace EM, Auwerx J, Decressac M. Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome. Brain. 2020 Jun 1;143(6):1686-1696. doi: 10.1093/brain/awaa105.