Ethanol impairs post-prandial hepatic protein metabolism.

Feo, Pierpaolo De; Volpi, Elena; Lucidi, Paola; Cruciani, Guido; Monacchia, Francesca; Reboldi, Gianpaolo; Santeusanio, Fausto; Bolli, Geremia B.; Brunetti, P

doi:10.1172/jci117818

Cited by 32 publications

(23 citation statements)

References 55 publications

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“…6 De Feo et al have shown that consumption of 3 or 4 glasses of wine over the course of a meal, an amount commonly consumed by social drinkers, is sufficient to significantly inhibit hepatic protein translation. 50 It has been previously shown that chronic ethanol consumption in mice alters the phosphorylation levels of mTOR, p70 S6 kinase, and 4E-BP1 in mouse cerebral cortex. 7 Chronic ethanol exposure in rats has also been shown to sequester eIF4E from the cap-complex, resulting from an increase in For personal use only.…”

Section: Discussionmentioning

confidence: 98%

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Hagner

Mazan-Mamczarz

Dai

et al. 2009

Blood

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Several epidemiologic studies support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin lymphoma. The observed lower risk among people who drank alcohol does not seem to vary with beverage type. The mechanisms accounting for alcohol-induced decrease in the incidence of lymphomas remain largely unknown. We demonstrate that low-dose chronic exposure to ethanol inhibits mammalian target of rapamycin (mTOR) C1 complex formation, resulting in decreased phosphorylation events involved in mTOR pathway signaling in a lymphoid-tissue specific manner. These changes in mTOR signaling lead to a decrease in eIF4E associated with the translation initiation complex and a repression of global capdependent synthesis in both lymphoma cell lines and normal donor lymphocytes. We show that chronic exposure of ethanol at physiologically relevant concentrations in a xenograft model results in a striking inhibition of lymphoma growth. IntroductionAlcohol abuse is associated with diseases of the liver, pancreas, and breast, and many other malignant disorders. 1,2 Interestingly, in contrast to solid tumors, several epidemiologic studies, including a large pooled analysis of case-control studies 3 and a recent cohort study, 4 indicate that persons who frequently consume small amounts of alcohol (1 or 2 drinks per day) have decreased risk of most types of non-Hodgkin lymphoma (NHL). The underlying biologic mechanism(s) for this negative association is (are) unknown at present.Ethanol decreases protein synthesis, and this effect is associated with changes in the phosphorylation status of several key components of the translational machinery. 5,6 Chronic alcohol intake is associated with disruption of the mammalian target of rapamycin (mTOR) signaling pathway; however, few mechanistic details are known about how ethanol interrupts this critical signaling pathway involved in translation. 7 mTOR forms 2 functionally distinct multiprotein serine/threonine kinase complexes, mTORC1 and mTORC2. The mTORC1 complex controls protein synthesis by phosphorylating key downstream effector molecules, the translational inhibitor protein 4E-BP1 and, p70 S6 kinase in response to sensory inputs, such as nutritional, growth factor, and cellular energy status. Activation of the p70 S6 kinase results in phosphorylation of the ribosomal protein S6 (RPS6) and allows its interaction with other ribosomal subunits and ribosomal biogenesis. 8 Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5Ј oligopyrimidine tract, which typically encode components of the protein synthesis machinery. 8 The signaling pathways that converge on mTOR are commonly activated in multiple human malignancies. The dysregulation of mTOR signaling leads to a selective increase in translation of messages that encode antiapoptotic proteins, activators of cell cycle progression, and growth factors, such as cyclin D1 and c-myc. 9,10 This underscores the importance of targeted inhibition of mTOR as...

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Section: Discussionmentioning

confidence: 98%

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Hagner

Mazan-Mamczarz

Dai

et al. 2009

Blood

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“…Enrichments and concentrations of plasma leucine and KIC were determined on their t-butyldimethylsilyl derivatives using gas chromatography-mass spectrometry in electron impact ionisation mode (GC8000, MS Voyager Finningan; ThermoQuest Italia, Milan, Italy), monitoring the ions 302 and 305 for leucine and 301 and 304 for KIC [14]. Plasma albumin and fibrinogen were purified as previously described in detail [15,16]. To evaluate plasma volume, serum samples were added with an equal volume of polyethylene glycol (∼4,000 Da; J. T. Baker, Deventer, Holland) solution (240 g/l) for precipitation of nonalbumin proteins.…”

Section: Methodsmentioning

confidence: 99%

Effects of dietary protein restriction on albumin and fibrinogen synthesis in macroalbuminuric type 2 diabetic patients

et al. 2007

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Aims/hypothesis Diabetic nephropathy is associated with hypoalbuminaemia and hyperfibrinogenaemia. A lowprotein diet has been recommended in patients with diabetic nephropathy, but its effects on albumin and fibrinogen synthesis are unknown. Methods We compared the effects of a normal (NPD; 1.38± 0.08 g kg −1 day −1 ) or low (LPD; 0.81±0.04 g kg −1 day −1 ) -protein diet on endogenous leucine flux (ELF), albumin and fibrinogen synthesis (L-[5,5,5,-2 H 3 ]leucine infusion), and markers of inflammation in nine type 2 diabetic patients with macroalbuminuria. Six healthy participants on NPD served as control participants. Results In comparison with healthy participants, type 2 diabetic patients on an NPD had similar ELF, reduced serum albumin (38±1.1 vs 42±0.8 g/l; p<0.05), similar fractional synthesis rates (FSR) and absolute synthesis rates (ASR) of albumin, and both increased plasma fibrinogen concentration [10.7±0.6 vs 7.2±0.5 μmol/l (3.64±0.22 vs 2.45±0.18 g/l); p<0.05] and fibrinogen ASR [11.03±1.17 vs 6.0±1.8 μmol 1.73 m −2 day −1 (3.7±0.4 vs 1.9±0.3 g 1.73 m −2 day −1 ); p< 0.01]. After LPD, type 2 diabetic patients had the following changes in comparison with NPD: reduced proteinuria (2.74±0.4 vs 4.51±0.8 g/day; p<0.05), ELF (1.93±0.08 vs 2.11±0.08 μmol kg −1 min −1 ; p<0.05) and total fibrinogen pool; increased serum albumin (42±1 vs 38±1 g/l; p<0.01) and albumin ASR (14.1±1 vs 9.9±1 g 1.73 m −2 day −1 ; p< 0.05); and reduced plasma IL-6 levels, which were correlated with albumin ASR (r=−0.749; p<0.05). Conclusions/interpretation LPD in type 2 diabetic patients with diabetic nephropathy reduces low-grade inflammatory state, proteinuria, albuminuria, whole-body proteolysis and ASR of fibrinogen, while increasing albumin FSR, ASR and serum concentration. ISRCTN ID no: CCT-NAPN-16911Keywords Absolute synthesis . Albumin . Diabetic nephropathy . Fibrinogen . Fractional synthesis . Leucine . Low-grade inflammation . Low-protein diet . Macroalbuminuria . Type 2 diabetes Abbreviations ASR absolute synthesis rate CRP C-reactive protein ELF endogenous leucine flux FSR fractional synthesis rate KIC α-ketoisocaproic acid LPD low-protein diet Diabetologia (2008) 51:21-28

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“…In a classic well-controlled study performed more than two decades ago in a metabolic ward, isoenergetic replacement of food energy by EtOH, given in the form of wine or pure EtOH, resulted in a persistent negative N balance, suggesting an effect of EtOH on fatfree-mass losses (MacDonald & Margen, 1976). More recently, it was demonstrated that elevation of blood EtOH following social drinking increased leucine turnover (Berneis et al 1997) and influenced hepatic protein metabolism (De Feo et al 1995;Volpi et al 1998). The effect of EtOH consumption on plasma leptin has not been investigated yet in human subjects.…”

Section: Other Metabolic Effects Of Alcoholmentioning

confidence: 99%

Role of substrate utilization and thermogenesis on body-weight control with particular reference to alcohol

Schütz

2000

Proc. Nutr. Soc.

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Alcohol (ethanol; EtOH) provides fuel energy to the body (29·7 kJ (7·1 kcal)/g, 23·4 kJ (5·6 kcal)/ml), as do other macronutrients, but no associated essential nutrients. The thermogenic effect of EtOH (on average 15 % of its metabolizable value) is much greater than that of the main substrates utilized by the body, i.e. fat and carbohydrates (CHO), suggesting a lower net efficiency of energy utilization for EtOH than for fat and CHO. EtOH cannot be stored in the body and is toxic, so that there is an obligatory continuous oxidation of EtOH and it becomes the priority fuel to be metabolized. In contrast to CHO, its rate of oxidation does not depend on the dose ingested. As with CHO intake, it engenders a shift in postprandial substrate utilization (decrease in fat oxidation), but by a non-insulin-mediated mechanism. A limited amount of EtOH can be converted to fatty acids by hepatic de novo lipogenesis (as occurs with high levels of CHO feeding) from acetate production, which inhibits lipolysis in peripheral tissues. There is no evidence that EtOH consumed under normoenergetic conditions (i.e. isoenergetically replacing CHO or fat) leads to greater body fat storage than fat or CHO. However, there is still a lack of experimental studies on the influence of EtOH on the level of spontaneous physical activity in man. This effect may well depend on the dose of EtOH consumed as well as other intrinsic factors.

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Ethanol impairs post-prandial hepatic protein metabolism.

Cited by 32 publications

References 55 publications

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Effects of dietary protein restriction on albumin and fibrinogen synthesis in macroalbuminuric type 2 diabetic patients

Role of substrate utilization and thermogenesis on body-weight control with particular reference to alcohol

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