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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 candidate gene expression with hepatic TG content.(A–B) Correlation of hepatic TG with expression levels of Gde1 (A) and Knop1 (B) in the liver. (C) Correlation of hepatic TG with expression levels of Gde1 in the white adipose tissue. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.017
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fig7: Correlation of candidate gene expression with hepatic TG content.(A–B) Correlation of hepatic TG with expression levels of Gde1 (A) and Knop1 (B) in the liver. (C) Correlation of hepatic TG with expression levels of Gde1 in the white adipose tissue. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.017

Mentions: The genetic variations underlying complex traits, such as steatosis, most often affect gene expression levels rather than structural (coding) aspects (Wang et al., 2005; Hindorff et al., 2009). Most of the large differences in gene expression are due to local differences (Orozco et al., 2012). Therefore, a useful approach to prioritizing candidate genes at a locus is to determine if the genes at the locus exhibit variation in expression that is controlled in cis. Such a variant is termed a cis-expression Quantitative Trait Locus (eQTL). We therefore identified significant cis-eQTL for liver and adipose for the genes in the chromosome 7 locus (Table 8). In addition, we asked whether the expression levels correlated with the clinical trait of interest (i.e., hepatic TG levels), since that would be consistent with a causal relationship. Among the candidate genes in the chromosome 7 locus, only three genes (Coq7, Gde1, and Knop1) have significant cis-eQTL and are also expressed in the liver (Tables 6, 8). These three genes also have significant cis-eQTL associations in adipose tissue (Table 8). The expression variation of these three candidate genes showed a continuous spectrum across the strains, indicating that the expression variations are not bimodal (data not shown). Hepatic TG levels correlated with Gde1 expression in both the liver (r = 0.35, p = 1.5 × 10−4) and adipose tissue (r = −0.21, p = 1.6 × 10−3) (Figure 7A,C). Likewise, Knop1 expression correlated with hepatic TG levels (r = 0.29, p = 2.5 × 10−2, Figure 7B) but not in the adipose tissue (r = 0.14, p = 0.133). On the other hand, hepatic TG levels did not correlate with Coq7 expression in the liver (r = 0.09, p = 0.368) or adipose tissue (r = −0.14, p = 0.142). Gde1 (also known as MIR16) encodes glycerophosphodiester phosphodiesterase 1, a ubiquitously expressed enzyme involved in phospholipid metabolism, whereas Knop1 encodes a lysine-rich nucleolar protein. Neither of these two genes has previously been identified in studies related to TG or lipid metabolism. We also examined coding variants for genes at the chromosome 7 locus using the PROVEAN prediction tool (Choi and Chan, 2015). A number of genes exhibited missense variants but these tended to be neutral and not likely to cause deleterious effects on protein stability and function (Table 9). Only the Q117R substitution in Syt7 was predicted to be deleterious. Syt7 (synaptotagmin VII) belongs to a protein family, which mediates Ca2+−dependent vesicular trafficking and exocytosis (Moghadam and& Jackson, 2013). Ablation of Syt7 has been shown to decrease insulin and glucagon secretion in pancreatic cells (Gustavsson et al., 2008, 2009).10.7554/eLife.05607.016Table 8.


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 candidate gene expression with hepatic TG content.(A–B) Correlation of hepatic TG with expression levels of Gde1 (A) and Knop1 (B) in the liver. (C) Correlation of hepatic TG with expression levels of Gde1 in the white adipose tissue. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.017
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fig7: Correlation of candidate gene expression with hepatic TG content.(A–B) Correlation of hepatic TG with expression levels of Gde1 (A) and Knop1 (B) in the liver. (C) Correlation of hepatic TG with expression levels of Gde1 in the white adipose tissue. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.017
Mentions: The genetic variations underlying complex traits, such as steatosis, most often affect gene expression levels rather than structural (coding) aspects (Wang et al., 2005; Hindorff et al., 2009). Most of the large differences in gene expression are due to local differences (Orozco et al., 2012). Therefore, a useful approach to prioritizing candidate genes at a locus is to determine if the genes at the locus exhibit variation in expression that is controlled in cis. Such a variant is termed a cis-expression Quantitative Trait Locus (eQTL). We therefore identified significant cis-eQTL for liver and adipose for the genes in the chromosome 7 locus (Table 8). In addition, we asked whether the expression levels correlated with the clinical trait of interest (i.e., hepatic TG levels), since that would be consistent with a causal relationship. Among the candidate genes in the chromosome 7 locus, only three genes (Coq7, Gde1, and Knop1) have significant cis-eQTL and are also expressed in the liver (Tables 6, 8). These three genes also have significant cis-eQTL associations in adipose tissue (Table 8). The expression variation of these three candidate genes showed a continuous spectrum across the strains, indicating that the expression variations are not bimodal (data not shown). Hepatic TG levels correlated with Gde1 expression in both the liver (r = 0.35, p = 1.5 × 10−4) and adipose tissue (r = −0.21, p = 1.6 × 10−3) (Figure 7A,C). Likewise, Knop1 expression correlated with hepatic TG levels (r = 0.29, p = 2.5 × 10−2, Figure 7B) but not in the adipose tissue (r = 0.14, p = 0.133). On the other hand, hepatic TG levels did not correlate with Coq7 expression in the liver (r = 0.09, p = 0.368) or adipose tissue (r = −0.14, p = 0.142). Gde1 (also known as MIR16) encodes glycerophosphodiester phosphodiesterase 1, a ubiquitously expressed enzyme involved in phospholipid metabolism, whereas Knop1 encodes a lysine-rich nucleolar protein. Neither of these two genes has previously been identified in studies related to TG or lipid metabolism. We also examined coding variants for genes at the chromosome 7 locus using the PROVEAN prediction tool (Choi and Chan, 2015). A number of genes exhibited missense variants but these tended to be neutral and not likely to cause deleterious effects on protein stability and function (Table 9). Only the Q117R substitution in Syt7 was predicted to be deleterious. Syt7 (synaptotagmin VII) belongs to a protein family, which mediates Ca2+−dependent vesicular trafficking and exocytosis (Moghadam and& Jackson, 2013). Ablation of Syt7 has been shown to decrease insulin and glucagon secretion in pancreatic cells (Gustavsson et al., 2008, 2009).10.7554/eLife.05607.016Table 8.

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