Influence of Dietary Zinc on Hepatic Collagen and Prolyl Hydroxylase Activity in Alcoholic Rats

Giménez, America; Caballería, Joan; Parés, Albert; Alié, S.; Deulofeu, R.; Andreu, Hernán; Rodés, Joan

doi:10.1002/hep.1840160331

Cited by 17 publications

(6 citation statements)

References 16 publications

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“…2A) and the previous reports on the elevated levels of HPH-2 in response to alcohol exposure, this enzyme does not seem to be the main reason for HIF-1α up-regulation, despite its critical role in the hydroxylation of HIF-1α needed for ubiquitin conjugation and subsequent degradation. For instance, alcohol administration was shown to increase the catalytic activities and levels of HPH, as reported by at least three different laboratories [40-42]. Therefore, it is more likely that the elevated levels of HIF-1α in alcohol-exposed mice (Fig.…”

Section: Discussionmentioning

confidence: 61%

Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans

Yun

Son

Abdelmegeed

et al. 2014

Free Radical Biology and Medicine

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Binge drinking, a common pattern of alcohol ingestion, is known to potentiate liver injury caused by chronic alcohol abuse. This study was aimed to investigate theeffects of acute binge alcohol onhypoxia-inducible factor-1α (HIF-1α)-mediated liver injury and rolesof alcohol metabolizing enzymes in alcohol-induced hypoxia and hepatotoxicity. Mice and human specimens assigned as binge or non-binge group were analyzed for blood alcohol concentration (BAC), alcohol metabolizing enzymes, HIF-1α-related protein nitration and apoptosis. Binge alcohol promoted acute liver injury in mice with elevated levels of ethanol-inducible cytochrome P450-2E1 (CYP2E1) and hypoxia, both of which were co-localized in centrilobular areas. We observed positive correlations among elevated BAC, CYP2E1, and HIF-1α in mice and humans exposed to binge alcohol. TheCYP2E1 protein levels(r=0.629, p=0.001) and activities (r=0.641, p=0.001) showed significantly positive correlation with BACs in human livers. HIF-1α levels were also positively correlated with BACs (r=0.745, p<0.001) or CYP2E1activities(r=0.792, p<0.001) in humans. Binge alcoholpromotedprotein nitration and apoptosis with significant correlations observed between inducible nitric oxide synthase and BACs, CYP2E1, or HIF-1α in human specimens. Binge alcohol-induced HIF-1α activation and subsequent protein nitration orapoptosisseen in wild-type were significantly alleviatedin the corresponding Cyp2e1-null mice while pretreatment with an HIF-1α inhibitor PX-478 prevented HIF-1α elevation with a trend of decreased levels of 3-nitrotyrosine and apoptosis, supporting the roles of CYP2E1and HIF-1α in binge alcohol-mediatedprotein nitration and hepatotoxicity. Thus binge alcohol promotes acute liver injury in mice and humans at least partly through a CYP2E1-HIF-1α-dependent apoptosis pathway.

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Section: Discussionmentioning

confidence: 61%

Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans

Yun

Son

Abdelmegeed

et al. 2014

Free Radical Biology and Medicine

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“…The mice were then divided into 4 groups, (1) Ctrl, (2) EtOH, (3) Zn and (4) EtOH+Zn, and continually fed for 4 weeks. For zinc supplementation, zinc sulfate was added to the liquid diet at 75 mg elemental zinc/L as described previously 9, 11. At the end of feeding experiment, the mice were anesthetized with Avertin (300 mg/kg) after 4 hrs fasting, and plasma, liver and GAD samples were harvested for assays.…”

Section: Methodsmentioning

confidence: 99%

“…Clinical studies demonstrated that zinc concentrations in both serum and liver were significantly reduced in patients with alcoholic steatosis, hepatitis and cirrhosis 6–8. Animal studies showed that dietary zinc supplementation attenuates alcohol-induced liver injury,9–13 suggesting the importance of zinc in progression of alcoholic liver disease. While the link between zinc and alcoholic steatosis has not been determined, increasing evidence suggest that zinc plays a critical role in regulation of hepatic lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Zinc Supplementation Reverses Alcohol-Induced Steatosis in Mice Through Reactivating Hepatocyte Nuclear Factor-4α and Peroxisome Proliferator-Activated Receptor-α†

et al. 2009

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Alcoholic steatosis is a fundamental metabolic disorder in the progression of alcoholic liver disease. Zinc deficiency is one of the most consistently observed biochemical/nutritional manifestations of alcoholic liver disease. The purpose of this study is to determine whether dietary zinc supplementation to mice previously exposed to alcohol could reverse alcoholic steatosis. Male 129S mice were pair-fed an alcohol or isocaloric maltose dextrin liquid diet for 16 weeks with or without dietary zinc supplementation for the last 4 weeks. Zinc supplementation significantly attenuated alcohol-mediated increases in hepatic triglyceride, cholesterol, and free fatty acids in association with accelerated hepatic fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Hepatic genes related to fatty acid oxidation and VLDL secretion were up-regulated by zinc supplementation, which was accompanied by restoring activity of hepatocyte nuclear factor-4␣ (HNF-4␣) and peroxisome proliferators

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“…The mice were then divided into four groups: (1) Ctrl, (2) EtOH, (3) Zn, and (4) EtOH+Zn, and continually fed for 4 weeks. For zinc supplementation, zinc sulfate was added to the liquid diet at 75 mg elemental Zn/L as described 9, 11. At the end of the feeding experiment, the mice were anesthetized with Avertin (300 mg/kg body weight) after 4 hours fasting, and plasma, liver, and gonadal adipose depot (GAD) samples were harvested for assays.…”

Section: Methodsmentioning

confidence: 99%

“…Clinical studies demonstrated that zinc concentrations in both serum and liver were significantly reduced in patients with alcoholic steatosis, hepatitis, and cirrhosis 6–8. Animal studies showed that dietary zinc supplementation attenuates alcohol‐induced liver injury,9–13 suggesting the importance of zinc in progression of alcoholic liver disease. Although the link between zinc and alcoholic steatosis has not been determined, increasing evidence suggest that zinc plays a critical role in regulation of hepatic lipid metabolism.…”

mentioning

confidence: 99%

In‐hospital outcomes of very elderly patients (85 years and older) undergoing percutaneous coronary intervention

Mack

2011

Cathet Cardio Intervent

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This study by Appleby and co-authors from Toronto is an important one and like most good research raises more questions than it answers. The study does confirm the impression of most clinicians that the mortality and morbidity of a coronary intervention in patients 85 years is significantly increased compared with younger patients. The authors found that the in-hospital mortality in these very elderly patients was six times higher than that in younger patients. While some of this excess mortality was due to a relatively low rate of elective percutaneous coronary intervention (PCI) procedures compared with patients under 85 years (25% vs. 47%), even after propensity matching the mortality was still double. What is noteworthy is that the mortality rate for elective PCI was 50 times higher (3% vs. 0.06%) in the very elderly compared with younger patients. The authors also found that major predictors of in-hospital mortality and MACE by multivariate logistic regression analysis included pre-existing renal impairment, severe left ventricular dysfunction, diabetes, and peripheral vascular disease. This study again raises the age old question of ''just because we can do it does that mean we should do it?'' Although the authors conclude that decisions to proceed with PCI in very elderly patients should be based on other prognostic variables and not on age alone, it appears that from this study the clinician should be very circumspect regarding intervention in the very elderly especially when cardiogenic shock, renal impairment, severe left ventricular dysfunction, and complex coronary lesions exist.The authors of this study examined only in-hospital mortality and outcomes. This raises additional questions that merit further study and answers. What was the 30-day mortality in this patient population? What was the discharge disposition compared to the patients' pre-hospital status? How many of these patients were alive at 1 year postprocedure, and what was their functional status? What is the burden on the healthcare system placed by intervening in these patients? What was the quality-adjusted life year (QALY) measure in this patient population?This study is an extremely important one and documents in a relatively large study sample the added mortality and morbidity associated with treating coronary disease in this very elderly population. What is needed next is the longitudinal follow-up that accurately assesses survival and functional outcome in QALYs gained in patients to justify intervention.

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Influence of Dietary Zinc on Hepatic Collagen and Prolyl Hydroxylase Activity in Alcoholic Rats

Cited by 17 publications

References 16 publications

Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans

Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans

Zinc Supplementation Reverses Alcohol-Induced Steatosis in Mice Through Reactivating Hepatocyte Nuclear Factor-4α and Peroxisome Proliferator-Activated Receptor-α†

In‐hospital outcomes of very elderly patients (85 years and older) undergoing percutaneous coronary intervention

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