The genetic architecture of NAFLD among inbred strains of mice.

Simon T Hui,Nikolaos Psychogios,Sarada Charugundla,Aldons J Lusis,Frode Norheim,Calvin Pan,Robert E Gerszten,Darwin L Dirks,Brian W Parks,Lawrence W Castellani,Todd Kirchgessner,Nam Che,Elin Org,Isaac Neuhaus,Peter S Gargalovic

doi:10.7554/elife.05607

Abstract

To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.

Highlights

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver abnormalities, ranging from benign hepatocellular accumulation of lipids, through non-alcoholic steatohepatitis (NASH), to fibrosis and cirrhosis in the absence of excessive consumption of alcohol and hepatitis viral infection
NAFLD is often referred to as the hepatic manifestation of metabolic syndrome, as it is associated with obesity, dyslipidemia, and insulin resistance (Lazo and& Clark, 2008)
Genes and chromosomes | Genomics and evolutionary biology body weight and fat accumulation in response to a HF/HS diet in mice is highly dependent on the genetic background of individual strains (Parks et al, 2013)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver abnormalities, ranging from benign hepatocellular accumulation of lipids (steatosis), through non-alcoholic steatohepatitis (NASH), to fibrosis and cirrhosis in the absence of excessive consumption of alcohol and hepatitis viral infection. Advanced NAFLD can eventually progress to end-stage liver disease with increased risk of hepatocellular carcinoma (HCC) (Kopec and Burns, 2011). Population studies have shown that NAFLD is strongly associated with obesity, diabetes, and dyslipidemia (Marchesini et al, 2003). NAFLD can be viewed as the hepatic manifestation of the metabolic syndrome. With the increasing prevalence of obesity, diabetes, and metabolic syndrome, it is not surprising that NAFLD is rapidly becoming the most common form of chronic liver disease worldwide (Ratziu et al, 2010). Simple steatosis appears to be benign and non-progressive in the

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