Accessible through:

Systems Genetics website: https://systems-genetics.org/CC_founders_NASH (redirects to Shiny application website)
Shiny application website: https://lisp-lms.shinyapps.io/CC_Founders_NASH/

Title:
The genetic background shapes disease susceptibility and reveal a specific role for mitochondrial dysfunction in the progression from NAFLD to NASH

Author list:
Giorgia Benegiamo (1), Giacomo von Alvensleben (1), Sandra Rodriguez-Lopez (1), Alexis Bachmann (1), Jean-David Morel (1), Ellen Broeckx (2), Jing Ying Ma (2), Vinicius Carreira (2), Sameh A. Youssef (2), Nabil Azhar (2), Dermot Reilly (2), Katharine D’Aquino (2), Shannon Mullican (2), Maroun Bou-Sleiman (1), Johan Auwerx (1)

Abstract:
Non-alcoholic steatohepatitis (NASH) is a global health concern that has still no treatment. The challenge in finding effective therapies is partly due to the lack of good mouse models and the complexity of the disease, characterized by the interplay between environmental and genetics factors. We tested the susceptibility of 7 genetically diverse mouse strains to develop NASH, by feeding them a western diet and housing them at thermoneutrality. Each strain responded to the environmental challenges, but the severity of their clinical phenotype varied widely across strains. The wild-derived PWK/PhJ mice were the most prone to develop NASH, while CAST/EiJ mice were completely resistant to hepatic histological alterations. We show that our experimental design is more suited than high-fat diet and room temperature housing to model human NASH. Levels of transcripts and proteins present in the mitochondria as well as mitochondrial function were robustly reduced in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, among the 7 strains tested, the alterations in gene expression observed in PWK/PhJ mice were the closest to the human NASH. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model that closely resembles the human disease.

Overview:
The aim of this app is to provide an easy access to the available data and results. The 3 main panels (Metadata, Phenotype explorer, Expression console) allow to respectively explore the metadata, the measured phenotypes and the genetic expression levels and correlation with the phenotypes.

Experimental design:
This study used 7 domesticated (C57BL/6J, DBA/2J, A/J, 129S1/SvlmJ) or wild-derived (CAST/EiJ, PWK/PhJ, WSB/EiJ) inbred mouse strains drawn from founders of the well-characterized BXD and collaborative cross panels, that are well known for their genetic diversity. Only male mice were used. The CC founder strains NOD/ShiLtJ and NZO/HlLtJ were excluded because they naturally develop diabetes and other symptoms in the absence of environmental challenges (Kollmus et al., 2020) (NOD: diabetes and immune defects, NZO: severe obesity and diabetes). The seven strains described above were housed at thermoneutrality (30°C = 86°F) from the age of 6 weeks. From the age of 7 weeks, the mice were fed either a Chow Diet (CD, Research Diets D16042904B) or a Western Diet (WD, Research Diets D12079B) to induce NAFLD and ultimately NASH. Each strain was split in 2 cohorts, with 1-3 strains per cohort and n = 6-8 mice per strain per condition, for a total of 96 samples. In vivo phenotyping was performed at multiple timepoints and mice were sacrificed at 1PM after a 4h fasting at the age of 24 weeks (see Figure).

Author affiliations:
1. Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
2. Janssen Research and Development, LLC

Updates to the Shiny application will directly be announced inside the application.
