Species Specificity of Arginine Deficiency-Induced Hepatic Steatosis

Milner, John A.; Hassan, Abdelmonem S.

doi:10.1093/jn/111.6.1067

Cited by 9 publications

(3 citation statements)

References 18 publications

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“…The inverse relationship between arginine levels and hepatic TG content may be due to increased arginine degradation in steatotic mice. Previous studies have shown that an arginine-deficient diet-induced hepatic steatosis in rats ( Milner and& Hassan, 1981 ). The levels of arginase 1, which catabolizes L-arginine to urea and L-ornithine, were increased in steatotic livers from mice fed a high-fat diet ( Eccleston et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

The genetic architecture of NAFLD among inbred strains of mice

Hui

Parks

Org

et al. 2015

eLife

117

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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.DOI: http://dx.doi.org/10.7554/eLife.05607.001

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Section: Discussionmentioning

confidence: 99%

The genetic architecture of NAFLD among inbred strains of mice

Hui

Parks

Org

et al. 2015

eLife

117

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“…Feeding an arginine-defi cient diet to rats leads to a marked fatty liver by an elevated plasma concentration of OA. Additionally, mice, hamsters, and rabbits were resistant to fatty liver largely because of their high urinary excretion rate of OA ( 45 ). Apart from this pharmacokinetic issue, no other information has been available concerning species-specifi c mechanisms of OA hepatotoxicity.…”

Section: Rapamycin Inhibits Oa-induced Fatty Livermentioning

confidence: 99%

Role of the AMPK/SREBP-1 pathway in the development of orotic acid-induced fatty liver

Jung

Kwon

Jung

et al. 2011

Journal of Lipid Research

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been used as a chemical inducer of fatty liver ( 2, 3 ). Although somewhat inconclusive, the reported mechanisms of OA-induced fatty liver include impairment of fatty acid oxidation, stimulation of lipogenesis, and reduction in lipid transport from the liver ( 4, 5 ). OA-induced fatty liver is species specifi c, and thus far, only the rat has been found to be susceptible. Durschlag and Robinson demonstrated that pharmacokinetic factors determined species specifi city in OA-induced hepatotoxicity ( 6 ). However, the precise molecular mechanism by which OA induces fat accumulation, specifi cally in the rat liver, has remained unclear. Identifi cation of molecular targets of OA effects and susceptibility are of great importance in terms of scientifi c as well as practical aspects. The major source of OA in a typical adult diet is milk and dairy products, which contribute about 0.005% of the total solids, a level at which rats do not show hepatic changes. However, considering the high content of OA in many dietary supplements, vitamin and mineral complexes, and muscle-building products widely sold on the market, we should be wary of possible health effects posed to humans.AMP-activated protein kinase (AMPK), a heterotrimeric enzyme complex, is the key regulator of energy metabolism in cells. The energy-sensing motif of the enzyme monitors the energy status of cells and controls its activity by phosphorylation at T172 ( 7 ). In the liver, activation of AMPK phosphorylates and inactivates the rate-limiting enzymes of lipogenesis, such as acetyl-CoA carboxylase (ACC) ( 8 ). AMPK is classically regulated by various metabolic stresses that cause an increase in the AMP/ATP ratio or Induction of fatty liver in rats by orotic acid (OA; 6-carboxyuracil) administration was fi rst observed in 1955 ( 1 ).

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“…Male Sprague-Dawley rats that are fed an argininedeficient diet for 21 days have significantly decreased rates of body weight gain but increased rates of hepatic lipid biosynthesis and urinary excretion of orotic acid and develop markedly fatty livers regardless of their age. 69 Supplementation of the arginine-deficient diet with 1% ribose, 1% hypoxanthine, or 0.2% adenine suppresses urinary orotic acid excretion and decreases the fatty infiltration, whereas supplementation with inosine, xanthine, or uracil does not. Although argininedeficient diets increase urinary orotic acid excretion in mice, hamsters, and rabbits, these species do not develop overtly fatty livers.…”

Section: Arginine-deficient Dietsmentioning

confidence: 99%

Animal Models of Steatosis

Koteish¹,

Diehl²

2001

Semin Liver Dis

408

295

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The lipid content of hepatocytes is regulated by the integrated activities of cellular enzymes that catalyze lipid uptake, synthesis, oxidation, and export. When "input" of fats into these systems (either because of increased fatty acid delivery, hepatic fatty acid uptake, or fatty acid synthesis) exceeds the capacity for fatty acid oxidation or export (i.e., "output"), then hepatic steatosis occurs. Genetic causes of increased fatty acid input promote excessive hepatic lipogenesis. These include mutations that cause leptin deficiency or leptin receptor inhibition and mutations that induce insulin, insulin-like growth factors, or insulin-responsive transcription factors. Genetic causes of impaired hepatic fatty acid oxidation inhibit the elimination (i.e., output) of fat from the liver. These include mutations that inhibit various components of the peroxisomal and/or mitochondrial pathways for fatty acid beta-oxidation. Environmental factors, such as diets and toxins, can also unbalance hepatic fatty acid synthesis and oxidation. Hepatic lipogenesis is increased by dietary sucrose, fructose, or fats and certain toxins, such as ethanol. Hepatic fatty acid oxidation is inhibited by choline- or methionine-deficient diets and other toxins, such as etomoxir. Animals with genetic or environmental induction of hepatic lipogenesis appear to be useful models for human nonalcoholic fatty liver disease in which hyperinsulinemia and defective leptin signaling are conspicuous at early stages of the disease process.

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Species Specificity of Arginine Deficiency-Induced Hepatic Steatosis

Cited by 9 publications

References 18 publications

The genetic architecture of NAFLD among inbred strains of mice

The genetic architecture of NAFLD among inbred strains of mice

Role of the AMPK/SREBP-1 pathway in the development of orotic acid-induced fatty liver

Animal Models of Steatosis

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