Dependence on dose of the acute effects of ethanol on liver metabolism in vivo.

Guynn, Robert W.; Pieklik, J R

doi:10.1172/jci108222

Cited by 62 publications

(14 citation statements)

References 32 publications

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“…This result also shows the advantage of imaging measurements compared with the common practice that measures tissue homogenates where tissue has been ground and mixed to be homogenized [61,72,73]. We observed high heterogeneity of the redox state in both coronal and transversal planes of PTEN-null pancreases and along tissue depth.…”

Section: Discussionsupporting

confidence: 58%

Imaging heterogeneity in the mitochondrial redox state of premalignant pancreas in the pancreas-specific PTEN-null transgenic mouse model

Nioka

2013

Biomark Res

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BackgroundMetabolic alteration is one of the hallmarks of carcinogenesis. We aimed to identify certain metabolic biomarkers for the early detection of pancreatic cancer (PC) using the transgenic PTEN-null mouse model. Pancreas-specific deletion of PTEN in mouse caused progressive premalignant lesions such as highly proliferative ductal metaplasia. We imaged the mitochondrial redox state of the pancreases of the transgenic mice approximately eight months old using the redox scanner, i.e., the nicotinamide adenine dinucleotide/oxidized flavoproteins (NADH/Fp) fluorescence imager at low temperature. Two different approaches, the global averaging of the redox indices without considering tissue heterogeneity along tissue depth and the univariate analysis of multi-section data using tissue depth as a covariate were adopted for the statistical analysis of the multi-section imaging data. The standard deviations of the redox indices and the histogram analysis with Gaussian fit were used to determine the tissue heterogeneity.ResultsAll methods show consistently that the PTEN deficient pancreases (Pdx1-Cre;PTENlox/lox) were significantly more heterogeneous in their mitochondrial redox state compared to the controls (PTENlox/lox). Statistical analysis taking into account the variations of the redox state with tissue depth further shows that PTEN deletion significantly shifted the pancreatic tissue to an overall more oxidized state. Oxidization of the PTEN-null group was not seen when the imaging data were analyzed by global averaging without considering the variation of the redox indices along tissue depth, indicating the importance of taking tissue heterogeneity into account for the statistical analysis of the multi-section imaging data.ConclusionsThis study reveals a possible link between the mitochondrial redox state alteration of the pancreas and its malignant transformation and may be further developed for establishing potential metabolic biomarkers for the early diagnosis of pancreatic cancer.

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Section: Discussionsupporting

confidence: 58%

Imaging heterogeneity in the mitochondrial redox state of premalignant pancreas in the pancreas-specific PTEN-null transgenic mouse model

Nioka

2013

Biomark Res

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“…and aldehyde dehydrogenase (EC 1.2.1.3) (1). This change in the redox state decreases the concentration of pyruvate and of other gluconeogenic intermediates (1,6,7), and inhibits gluconeogenesis from substrates such as lactate (1,3,8), glycerol (1, s), and gluconeogenic amino acids ( 1 ).…”

mentioning

confidence: 99%

Ethanol Stimulates Glycogenosis in Livers from Fed Rats

Kubota

Virkamäki

Yki‐Järvinen

1992

Experimental Biology and Medicine

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To determine the reason for the lack of a hypoglycemic effect of ethanol in the fed state, the effect of ethanol on glucose turnover, liver glycogenolysis, and glucose metabolites was determined. Chronically catheterized awake and freely moving fed rats received either ethanol (blood ethanol, 37 +/- 10 mmol/liter, n = 11) or saline (n = 13) intravenously for 4 hr. Glucose turnover was determined using a primed continuous infusion of [3-3H]glucose. The liver was freeze clamped at 4 hr for glycogen and metabolite measurements. Plasma glucose (5.8 +/- 0.3 mmol/liter vs 6.3 +/- 0.2 mmol/liter at 4 hr, ethanol versus saline) and the rate of glucose turnover (61 +/- 9 vs 58 +/- 8 moles/kg.min) were similar during the ethanol and saline infusions. Plasma lactate was significantly higher in the ethanol (1.32 +/- 0.05 mmol/liter) than in the saline (0.86 +/- 0.06 mmol/liter, P less than 0.001) study. Concentrations of gluconeogenic intermediates in the liver (glucose 6-phosphate, fructose 6-phosphate, glucose 1-phosphate, and pyruvate) were all significantly and -30% lower in ethanol-infused than in saline-infused rats. The liver citrate content was similar in ethanol-infused than in saline-infused rats. The liver citrate content was similar in ethanol (0.38 +/- 0.03 mmol/liter) and saline (0.37 +/- 0.04 mmol/liter) studies. Liver glycogen was 75% lower in the ethanol-infused (61 +/- 9 mmol/kg dry wt) than the saline (242 +/- 27 mmol/kg dry wt, P less than 0.001)-infused rats. These data demonstrate that in fed rats given ethanol, glucose turnover is maintained constant by accelerated glycogenolysis. Thus, inhibition of gluconeogenesis by ethanol does not lower hepatic glucose production unless compensatory glycogenolysis can be prevented.

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“…It is not clear whether similar mechanisms are responsible for both the acute and chronic effects. Little is known about the effects of ethanol on SAM and SAH at very early time points; it is possible that the SAM/SAH ratio decreases transiently as an early response to ethanol exposure, coincident with an early shift in the NADH/NAD + ratio [7]. The shift in the NADH/NAD + ratio tends to be less pronounced in chronic ethanol exposure models than in acute models [25,26] as a result of increased re-oxidation of NADH and/or increased metabolism of ethanol through enzymes other than alcohol dehydrogenase [27].…”

Section: Discussionmentioning

confidence: 99%

Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD+ system

Watson

Song

Kirpich

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Methionine metabolism is disrupted in patients with alcoholic liver disease, resulting in altered hepatic concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and other metabolites. The present study tested the hypothesis that reductive stress mediates the effects of ethanol on liver methionine metabolism. Isolated rat livers were perfused with ethanol or propanol to induce a reductive stress by increasing the NADH/NAD+ ratio, and the concentrations of SAM and SAH in the liver tissue were determined by high-performance liquid chromatography. The increase in the NADH/NAD+ ratio induced by ethanol or propanol was associated with a marked decrease in SAM and an increase in SAH liver content. 4-Methylpyrazole, an inhibitor the NAD+-dependent enzyme alcohol dehydrogenase, blocked the increase in the NADH/NAD+ ratio and prevented the alterations in SAM and SAH. Similarly, co-infusion of pyruvate, which is metabolized by the NADH-dependent enzyme lactate dehydrogenase, restored the NADH/NAD+ ratio and normalized SAM and SAH levels. The data establish an initial link between the effects of ethanol on the NADH/NAD+ redox couple and the effects of ethanol on methionine metabolism in the liver.

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Dependence on dose of the acute effects of ethanol on liver metabolism in vivo.

Cited by 62 publications

References 32 publications

Imaging heterogeneity in the mitochondrial redox state of premalignant pancreas in the pancreas-specific PTEN-null transgenic mouse model

Imaging heterogeneity in the mitochondrial redox state of premalignant pancreas in the pancreas-specific PTEN-null transgenic mouse model

Ethanol Stimulates Glycogenosis in Livers from Fed Rats

Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD+ system

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