Genetic control of the NAFLD/NASH transition
Description: Non-alcoholic fatty liver disease (NAFLD) represents a global health burden with environmental, genetic and epigenetic factors being implicated in its onset and progression to non-alcoholic steatohepatitis (NASH). Recent evidence suggests that NAFLD/NASH and liver aging share features such as changes in cellular composition, accumulation of somatic mutations, telomere shortening, increase in senescent cells, loss of proteostasis, altered mitochondrial activity and changes in the metabolome and lipidome. Current animal models are often restricted to a single genetic background and poorly recapitulate the full clinical spectrum of human NAFLD and NASH or their hallmarks, such as hepatocyte ballooning and fibrosis. Based on our characterization of 7 Collaborative Cross (CC) founder strains––C57BL6/J, DBA2J, A/J, 129S1/SvlmJ, WSB/EiJ, CAST/EiJ and PWK/PhJ––we selected strains susceptible (C57BL/6J, 129S1/SvlmJ and PWK/PhJ) and resistant (CAST/EiJ) to NAFLD/NASH and generated a 4-way F2 intercross. The goal of our project is to map causal genes and pathways driving pathogenesis and progression of NAFLD/NASH in this population, then link these pathways with healthspan traits and evaluate their translational potential through an exploration of human genetic databases, in vitro and in vivo studies. Our plan will achieve the following aims: Aim 1:Map genes and gene networks that predispose to NAFLD/NASH. We will expand an existing resource of metabolic and liver phenotypes of 500 mice––both males and females––from a 4-way cross between inbred strains that are highly susceptible (PWK/PhJ), susceptible (C57BL6/J and 129S1/SvlmJ) and protected (CAST/EiJ) from liver disease. All mice were fed a western diet (WD) in thermoneutral (TN) conditions for 4 months, which was sufficient to trigger liver disease in the susceptible strains. Clinical phenotypes, liver transcriptome, and liver histology are already generated. Here, we plan to add other measurements including epigenomics, proteomics, metabolomics, and lipidomics, to define multi-omic signatures of liver health and uncover robust connections between genetic variants, molecular traits, and clinically relevant phenotypes. Bioinformatic and statistical frameworks, previously developed in our group, will then define associated genomic regions and identify candidate genes and networks that underpin liver health. The deliverable of Aim 1 is the generation of a multi-omic resource for liver health and the prioritization of genes and pathways for further mechanistic and validation studies.Aim 2: Establish how aging pathways relate to NAFLD/NASH. Epidemiological and molecular evidence suggest that aging is the most important risk factor for many chronic non-communicable disease (NCDs) and recent studies show that NASH is associated with epigenetic age acceleration. We hypothesize that NAFLD/NASH is a model of accelerated liver aging. We will therefore characterize mitochondrial phenotypes (bioenergetics, NAD homeostasis, heteroplasmy, dynamics, mitochondrial stress response), DNA phenotypes (methylation, accessibility, somatic mutations, telomere length), proteostasis (aggregates, chaperones, proteases, auto/mitophagy, proteasomes) and senescence pathways and determine whether they can modulate the pathogenesis and progression of NAFLD/NASH. Quantifying and understanding how accelerated aging contributes to chronic liver disease is hence the deliverable of Aim 2.Aim 3:Mechanistically validate and clinically translate regulators of liver disease. Using bioinformatics and loss-of-function (LOF) strategies in primary mouse and human liver cells, liver organoids, and mice, we will mechanistically validate a selected number of candidate genes/networks. We will evaluate the translational relevance of candidates by associating genetic variants in candidate genes with metabolic and liver phenotypes in resources such as the UK or Estonian Biobanks. In addition to single gene association tests, we will apply network-based and gene-gene interactions tests that will rely on networks that emerge from Aim 1 and 2. The identification of validated and clinically relevant regulators of NCDs of the liver will be the deliverable of Aim 3.
Amount: CHF 960,000
Funding type: research
Funder scheme: Project funding
Start date: 2023-07-01
End date: 2027-06-30
Investigator: Auwerx, Johan
Institution: EPF Lausanne – EPFL
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: 214826
OpenAlex ID: G90541347