The genetic architecture of NAFLD among inbred strains of mice

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.DOI: http://dx.doi.org/10.7554/eLife.05607.001

Genetic and hormonal control of hepatic steatosis in female and male mice

“…We have previously shown a significant enrichment in mitochondria genes among the transcripts with the highest correlation with hepatic TG in male mice (24). As seen for males when we performed enrichment analysis using the DAVID GO program (32) on the 1,000 liver genes mostly correlated to hepatic TG in females, we identified a significant enrichment in mitochondria genes (Fig.…”

“…We have previously described genetic and environmental factors contributing to hepatic steatosis in 113 strains of male mice (24). To study the factors contributing to hepatic steatosis in females, we fed female mice from 100 strains of the HMDP a HF/HS diet for 8 weeks before quantifying hepatic lipid content.…”

“…All 100 female and 113 male mouse strains included in the study were obtained from Jackson Laboratory and have been described in detail previously (23,24). The experimental design of the HF/ HS feeding study has also been described previously (25).…”

“…The number of livers per female strain is included in supplemental Table 1. The number of livers done per male strain has been described previously (24).…”

“…RNA was isolated from liver and gonadal adipose tissue as described previously (24). Briefly, tissue was homogenized in Qiazol and RNA was isolated using RNeasy columns (Qiagen, Valencia, CA).…”