Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

Frode Norheim,Christian A Drevon,Brian W Parks,Marcus M Seldin,Thomas Bjellaas,Jennifer Lang,Knut T Dalen,Calvin Pan,Laurent Vergnes,Aldons J Lusis,Margarete Mehrabian,Yonghong Meng,Karen Reue,James A Ward,Simon T Hui,Miklós Péterfy,Thomas E Gundersen,Karthickeyan Chella Krishnan

doi:10.15252/msb.20209684

Abstract

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high‐fat/high‐sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.

Highlights

Maintenance of hepatic lipid homeostasis is critical for many physiologic processes (Musso et al, 2018; Svegliati-Baroni et al, 2019)
We report a new resource for investigation of genetic regulation of the hepatic lipidome and its relationship to hepatic steatosis (Hui et al, 2015), insulin resistance (Parks et al, 2015), obesity (Parks et al, 2013), plasma lipids, and gut bacteria (Parks et al, 2013) in mice fed a high-fat/high-sucrose (HF/HS) diet for 8 weeks
Correlation, and network analyses, we identified several novel pathways regulating hepatic lipid levels and provide experimental validation to define their roles in diet-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance

Summary

Introduction

Maintenance of hepatic lipid homeostasis is critical for many physiologic processes (Musso et al, 2018; Svegliati-Baroni et al, 2019). Recent advances in global lipidomics by mass spectrometry have allowed a more comprehensive view of the hepatic lipidome (Gorden et al, 2015; Yang et al, 2018) These analyses have highlighted the complexity of lipid species and generated correlative links to several chronic diseases (Gorden et al, 2015; Luukkonen et al, 2016; Peng et al, 2018). Systems genetics provides an alternative approach for unbiased hypothesis generation based on natural genetic variation, using DNA variation as a directional anchor This is accomplished by monitoring clinical traits and molecular information (such as gene expression or lipidomics) in a genetically diverse population and analyzing the results using genome-wide association (GWA), correlation structure, and network modeling (Civelek & Lusis, 2014)

Methods

Results

Conclusion