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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

Correlation of hepatic TG content with adiposity and fat mass.(A–E) Correlation of hepatic TG with adiposity (A), subcutaneous fat (B), gonadal fat (C), mesenteric fat (D), and retroperitoneal fat (E). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.006
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fig4: Correlation of hepatic TG content with adiposity and fat mass.(A–E) Correlation of hepatic TG with adiposity (A), subcutaneous fat (B), gonadal fat (C), mesenteric fat (D), and retroperitoneal fat (E). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.006

Mentions: Increased adiposity has been linked to the incidence of NAFLD in humans. Consistent with this finding, there was a robust correlation between hepatic TG levels and adiposity (r = 0.59, p = 6.70 × 10−35, Figure 4A). We dissected the individual fat depots and found that steatosis was associated with increased subcutaneous, gonadal and mesenteric fat mass but not with retroperitoneal fat content (Figure 4B–E). The aforementioned p-values were not adjusted for multiple testing since the correlation analyses were performed based on knowledge of potential association between NAFLD and those clinical traits (e.g., insulin resistance, plasma lipids, and adiposity). Nevertheless, the correlations remained significant after Bonferroni correction for all measured traits.10.7554/eLife.05607.006Figure 4.Correlation of hepatic TG content with adiposity and fat mass.


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)

Correlation of hepatic TG content with adiposity and fat mass.(A–E) Correlation of hepatic TG with adiposity (A), subcutaneous fat (B), gonadal fat (C), mesenteric fat (D), and retroperitoneal fat (E). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.006
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Correlation of hepatic TG content with adiposity and fat mass.(A–E) Correlation of hepatic TG with adiposity (A), subcutaneous fat (B), gonadal fat (C), mesenteric fat (D), and retroperitoneal fat (E). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.006
Mentions: Increased adiposity has been linked to the incidence of NAFLD in humans. Consistent with this finding, there was a robust correlation between hepatic TG levels and adiposity (r = 0.59, p = 6.70 × 10−35, Figure 4A). We dissected the individual fat depots and found that steatosis was associated with increased subcutaneous, gonadal and mesenteric fat mass but not with retroperitoneal fat content (Figure 4B–E). The aforementioned p-values were not adjusted for multiple testing since the correlation analyses were performed based on knowledge of potential association between NAFLD and those clinical traits (e.g., insulin resistance, plasma lipids, and adiposity). Nevertheless, the correlations remained significant after Bonferroni correction for all measured traits.10.7554/eLife.05607.006Figure 4.Correlation of hepatic TG content with adiposity and fat mass.

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