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The genetic architecture of NAFLD among inbred strains of mice.

Hui ST, Parks BW, Org E, Norheim F, Che N, Pan C, Castellani LW, Charugundla S, Dirks DL, Psychogios N, Neuhaus I, Gerszten RE, Kirchgessner T, Gargalovic PS, Lusis AJ - Elife (2015)

Bottom Line: Genome-wide association studies revealed three loci associated with hepatic TG accumulation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of genetic background on hepatic TG accumulation.(A) Hepatic TG levels in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of hepatic TG with liver weight (B), hepatic total cholesterol (TC) (C), and hepatic phospholipid (D). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.003
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fig1: Effects of genetic background on hepatic TG accumulation.(A) Hepatic TG levels in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of hepatic TG with liver weight (B), hepatic total cholesterol (TC) (C), and hepatic phospholipid (D). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.003

Mentions: 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). The development of NAFLD is strongly influenced by both dietary and genetic factors. We previously showed that the increase in 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). To study the gene-by-diet effects on hepatic steatosis, a panel of 8-week-old male HMDP mice were fed a HF/HS diet for 8 weeks to induce obesity and steatosis (Parks et al., 2013). Lipids were extracted and quantified in 478 individual livers from 113 strains of male mice. A wide spectrum of hepatic TG content was observed among the strains with more than 30-fold difference between the high and low responders (Figure 1A and Supplementary file 1). Hepatic TG content was significantly correlated with the liver weight (r = 0.38, p = 5.75 × 10−14, Figure 1B). Contrary to the large variations in TG among strains, less than threefold difference in cholesterol and phospholipid levels was observed among the strains (Supplementary file 1). Modest correlations between these lipids with hepatic TG were observed. The TG content in the liver was positively correlated with hepatic total cholesterol (TC) content (r = 0.35, p = 1.18 × 10−12, Figure 1C) but negatively correlated with the levels of phospholipids (r = −0.26, p = 3.45 × 10−7, Figure 1D). These data suggest that increased neutral lipids content, in particular TG, contributes significantly to the enlarged livers.10.7554/eLife.05607.003Figure 1.Effects of genetic background on hepatic TG accumulation.


The genetic architecture of NAFLD among inbred strains of mice.

Hui ST, Parks BW, Org E, Norheim F, Che N, Pan C, Castellani LW, Charugundla S, Dirks DL, Psychogios N, Neuhaus I, Gerszten RE, Kirchgessner T, Gargalovic PS, Lusis AJ - Elife (2015)

Effects of genetic background on hepatic TG accumulation.(A) Hepatic TG levels in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of hepatic TG with liver weight (B), hepatic total cholesterol (TC) (C), and hepatic phospholipid (D). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.003
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493743&req=5

fig1: Effects of genetic background on hepatic TG accumulation.(A) Hepatic TG levels in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of hepatic TG with liver weight (B), hepatic total cholesterol (TC) (C), and hepatic phospholipid (D). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.003
Mentions: 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). The development of NAFLD is strongly influenced by both dietary and genetic factors. We previously showed that the increase in 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). To study the gene-by-diet effects on hepatic steatosis, a panel of 8-week-old male HMDP mice were fed a HF/HS diet for 8 weeks to induce obesity and steatosis (Parks et al., 2013). Lipids were extracted and quantified in 478 individual livers from 113 strains of male mice. A wide spectrum of hepatic TG content was observed among the strains with more than 30-fold difference between the high and low responders (Figure 1A and Supplementary file 1). Hepatic TG content was significantly correlated with the liver weight (r = 0.38, p = 5.75 × 10−14, Figure 1B). Contrary to the large variations in TG among strains, less than threefold difference in cholesterol and phospholipid levels was observed among the strains (Supplementary file 1). Modest correlations between these lipids with hepatic TG were observed. The TG content in the liver was positively correlated with hepatic total cholesterol (TC) content (r = 0.35, p = 1.18 × 10−12, Figure 1C) but negatively correlated with the levels of phospholipids (r = −0.26, p = 3.45 × 10−7, Figure 1D). These data suggest that increased neutral lipids content, in particular TG, contributes significantly to the enlarged livers.10.7554/eLife.05607.003Figure 1.Effects of genetic background on hepatic TG accumulation.

Bottom Line: Genome-wide association studies revealed three loci associated with hepatic TG accumulation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.

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.

No MeSH data available.


Related in: MedlinePlus