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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 and polar metabolites in the plasma.Correlation of hepatic TG with plasma levels of arginine (A), ornithine (B), citrulline (C), TMANO (D), creatine (E), and creatinine (F). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.021
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fig10: Correlation of hepatic TG and polar metabolites in the plasma.Correlation of hepatic TG with plasma levels of arginine (A), ornithine (B), citrulline (C), TMANO (D), creatine (E), and creatinine (F). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.021

Mentions: To identify metabolites associated with hepatic steatosis, we employed a metabolomic approach to measure 47 metabolites (amino acids, amines, and other polar compounds, Supplementary file 2) in the plasma of mice after 8 weeks of HF/HS feeding. Correlation analysis revealed a significant negative relationship between hepatic TG levels and plasma levels of arginine (r = −0.53, p = 9.85 × 10−12) and its degradative metabolite ornithine (r = −0.18, p = 0.027) (Figure 10A,B), whereas citrulline, another degradative metabolite of arginine, showed a positive correlation with hepatic TG content (r = 0.18, p = 0.034, Figure 10C). Hepatic TG levels were positively correlated with plasma levels of trimethylamine-N-oxide (TMANO, r = 0.18, p = 0.034, Figure 10D). Increased TMANO levels have previously been implicated in the susceptibility of strain 129S6 mice to diet-induced impaired glucose homeostasis and NAFLD (Dumas et al., 2006). TMANO is an oxidative product of trimethylamine (TMA), a metabolite of choline in animals. TMANO levels are regulated by both genetic and dietary factors and are strongly associated with atherosclerosis (Bennett et al., 2013). The oxidation of TMA is catalyzed by the hepatic flavin-containing monooxygenase (FMO) family of enzymes with FMO3 having the highest catalytic activity. No significant correlation between FMO3 expression and hepatic TG content was observed; however, among the 5 members in the FMO family, FMO5 expression exhibited a significant correlation with hepatic TG content (r = 0.46, p = 2.71 × 10−7). Hepatic TG content was also positively associated with plasma creatine (r = 0.23, p = 6 × 10−3, Figure 10E) and creatinine levels (r = 0.25, p = 6 × 10−3, Figure 10F).10.7554/eLife.05607.021Figure 10.Correlation of hepatic TG and polar metabolites in the plasma.


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 and polar metabolites in the plasma.Correlation of hepatic TG with plasma levels of arginine (A), ornithine (B), citrulline (C), TMANO (D), creatine (E), and creatinine (F). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.021
© Copyright Policy
Related In: Results  -  Collection

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

fig10: Correlation of hepatic TG and polar metabolites in the plasma.Correlation of hepatic TG with plasma levels of arginine (A), ornithine (B), citrulline (C), TMANO (D), creatine (E), and creatinine (F). r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.021
Mentions: To identify metabolites associated with hepatic steatosis, we employed a metabolomic approach to measure 47 metabolites (amino acids, amines, and other polar compounds, Supplementary file 2) in the plasma of mice after 8 weeks of HF/HS feeding. Correlation analysis revealed a significant negative relationship between hepatic TG levels and plasma levels of arginine (r = −0.53, p = 9.85 × 10−12) and its degradative metabolite ornithine (r = −0.18, p = 0.027) (Figure 10A,B), whereas citrulline, another degradative metabolite of arginine, showed a positive correlation with hepatic TG content (r = 0.18, p = 0.034, Figure 10C). Hepatic TG levels were positively correlated with plasma levels of trimethylamine-N-oxide (TMANO, r = 0.18, p = 0.034, Figure 10D). Increased TMANO levels have previously been implicated in the susceptibility of strain 129S6 mice to diet-induced impaired glucose homeostasis and NAFLD (Dumas et al., 2006). TMANO is an oxidative product of trimethylamine (TMA), a metabolite of choline in animals. TMANO levels are regulated by both genetic and dietary factors and are strongly associated with atherosclerosis (Bennett et al., 2013). The oxidation of TMA is catalyzed by the hepatic flavin-containing monooxygenase (FMO) family of enzymes with FMO3 having the highest catalytic activity. No significant correlation between FMO3 expression and hepatic TG content was observed; however, among the 5 members in the FMO family, FMO5 expression exhibited a significant correlation with hepatic TG content (r = 0.46, p = 2.71 × 10−7). Hepatic TG content was also positively associated with plasma creatine (r = 0.23, p = 6 × 10−3, Figure 10E) and creatinine levels (r = 0.25, p = 6 × 10−3, Figure 10F).10.7554/eLife.05607.021Figure 10.Correlation of hepatic TG and polar metabolites in the plasma.

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