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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

Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.(A) Plasma alanine aminotransferase (ALT) activities in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of plasma ALT activities with hepatic triglyceride (B), hepatic Ptprc (Cd45r) expression (C) and hepatic. Cd68 expression. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.004
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fig2: Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.(A) Plasma alanine aminotransferase (ALT) activities in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of plasma ALT activities with hepatic triglyceride (B), hepatic Ptprc (Cd45r) expression (C) and hepatic. Cd68 expression. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.004

Mentions: To assess liver damage, we measured alanine aminotransferase (ALT) enzyme activity in the plasma (Figure 2A). Similar to hepatic TG content, we also observed a large variation in ALT activities among the strains. Plasma ALT activities showed a positive correlation with hepatic TG levels, implicating a role of increased hepatic TG levels in liver damage (Figure 2B). ALT is an established biochemical and clinical marker for liver damage as this enzyme is released into the circulation when the integrity of the cell membrane of hepatocytes is compromised. We performed histologic examination of livers from a subset of strains including some with high TG and did not observe evidence of significant pathology other than lipid accumulation (data not shown). Furthermore, mRNA levels of markers for B-lymphocytes (CD45/PTPPRC) and macrophages (CD68) were not increased in steatotic liver samples (Figure 2C,D). Similarly, markers for other immune cells, such as T cells (Cd28, Csf2, Cd4, Ccr5, Gata3 Cxcr4), B cells (Pax5, Cd70, Cd79b), and leukocytes (Cd33, Cd52, Cd53, Cd44, Prg2) were also not increased (data not shown), suggesting the absence of significant immune cell infiltration and steatohepatitis in these mice after 8 weeks on the HF/HS diet.10.7554/eLife.05607.004Figure 2.Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.


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)

Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.(A) Plasma alanine aminotransferase (ALT) activities in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of plasma ALT activities with hepatic triglyceride (B), hepatic Ptprc (Cd45r) expression (C) and hepatic. Cd68 expression. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.004
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.(A) Plasma alanine aminotransferase (ALT) activities in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of plasma ALT activities with hepatic triglyceride (B), hepatic Ptprc (Cd45r) expression (C) and hepatic. Cd68 expression. r, biweight midcorrelation; p, p-value.DOI:http://dx.doi.org/10.7554/eLife.05607.004
Mentions: To assess liver damage, we measured alanine aminotransferase (ALT) enzyme activity in the plasma (Figure 2A). Similar to hepatic TG content, we also observed a large variation in ALT activities among the strains. Plasma ALT activities showed a positive correlation with hepatic TG levels, implicating a role of increased hepatic TG levels in liver damage (Figure 2B). ALT is an established biochemical and clinical marker for liver damage as this enzyme is released into the circulation when the integrity of the cell membrane of hepatocytes is compromised. We performed histologic examination of livers from a subset of strains including some with high TG and did not observe evidence of significant pathology other than lipid accumulation (data not shown). Furthermore, mRNA levels of markers for B-lymphocytes (CD45/PTPPRC) and macrophages (CD68) were not increased in steatotic liver samples (Figure 2C,D). Similarly, markers for other immune cells, such as T cells (Cd28, Csf2, Cd4, Ccr5, Gata3 Cxcr4), B cells (Pax5, Cd70, Cd79b), and leukocytes (Cd33, Cd52, Cd53, Cd44, Prg2) were also not increased (data not shown), suggesting the absence of significant immune cell infiltration and steatohepatitis in these mice after 8 weeks on the HF/HS diet.10.7554/eLife.05607.004Figure 2.Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.

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