Zinc Supplementation Enhances Hepatic Regeneration by Preserving Hepatocyte Nuclear Factor-4α in Mice Subjected to Long-Term Ethanol Administration

Kang, X.; Song, Zhenyuan; McClain, Craig J.; Kang, Y. James; Zhou, Zhanxiang

doi:10.2353/ajpath.2008.070631

Cited by 35 publications

(26 citation statements)

References 52 publications

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“…Dysfunction of hepatic HNF-4␣ has been documented in disease conditions such as cirrhosis (7), hepatocellular carcinoma (19), and alcoholic liver disease (14). In a tumor progression mouse model, the highly invasive fast-growing dedifferentiated variant (fgHCC) exhibited loss of characteristic hepatocyte markers in association with loss of HNF-4␣ expres- sion (19).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of hepatocyte nuclear factor-4α mediates alcohol-induced downregulation of intestinal tight junction proteins

Zhong

Zhao

McClain

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Chronic alcohol exposure has been shown to increase the gut permeability in the distal intestine, in part, through induction of zinc deficiency. The present study evaluated the molecular mechanisms whereby zinc deficiency mediates alcohol-induced intestinal barrier dysfunction. Examination of zinc finger transcription factors in the gastrointestinal tract of mice revealed a prominent distribution of hepatocyte nuclear factor-4alpha (HNF-4alpha). HNF-4alpha exclusively localizes in the epithelial nuclei and exhibited an increased abundance in mRNA and protein levels in the distal intestine. Chronic alcohol exposure to mice repressed the HNF-4alpha gene expression in the ileum and reduced the protein level and DNA binding activity of HNF-4alpha in all of the intestinal segments with the most remarkable changes in the ileum. Chronic alcohol exposure also decreased the mRNA levels of tight junction proteins, particularly in the ileum. Caco-2 cell culture studies were conducted to determine the role of HNF-4alpha in regulation of the epithelial tight junction and barrier function. Knockdown of HNF-4alpha in Caco-2 cells decreased the mRNA and protein levels of tight junction proteins in association with disruption of the epithelial barrier. Alcohol treatment inactivated HNF-4alpha, which was prevented by N-acetyl-cysteine or zinc. The link between zinc and HNF-4alpha function was confirmed by zinc deprivation, which inhibited HNF-4alpha DNA binding activity. These results indicate that inactivation of HNF-4alpha due to oxidative stress and zinc deficiency is likely a novel mechanism contributing to the deleterious effects of alcohol on the tight junctions and the intestinal barrier function.

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Section: Discussionmentioning

confidence: 99%

Inactivation of hepatocyte nuclear factor-4α mediates alcohol-induced downregulation of intestinal tight junction proteins

Zhong

Zhao

McClain

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Hepatocyte nuclear factor-4α (HNF-4α), a Zn finger protein, is a liver enriched transcription factor, has been reported to bind the promoters of more than 1000 genes involved in most aspects of hepatocyte function including cell proliferation [166].…”

Section: Studied Variables Fementioning

confidence: 99%

Study of Serum Copper and Iron in Children with Chronic Liver Diseases

Ibrahim¹

2013

Anat Physiol

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Trace elements have a major role as both oxidants and antioxidants, promoting and protecting from tissue damage respectively. As the liver has a pivotal role in trace elements metabolism and consequenyly their bioavailability, we aimed to measure serum levels of essential trace elements in children with chronic liver diseases (CLDs) regardless the etiology and to study their correlation with liver function tests. Serum zinc (Zn), copper (Cu) and iron (Fe); together with other trace elements parameters; were measured in 50 children with CLDs using spectrophotometry and their levels were compared with those age and sex matched healthy children as controls. Serum Cu, Fe, ferritin and transferrin saturation (TS) were significantly higher in the CLDs group than that in the control group; while serum Zn and total iron binding capacity (TIBC) were significantly lower in the CLDs than that in the control group. Serum Fe, Cu, TS and ferritin were positively correlated with biochemical parameters of liver damage; while serum Zn and TIBC were negatively correlated with biochemical parameters of liver damage. These results encourage inclusion of serum Zn, Cu and Fe as biomarkers for monitoring the severity of liver damage during routine assessment of children with CLDs. We recommended caution to avoid excess Fe and Cu intake in children with CLDs. Moreover, Zn supplementation could be encouraged in children with CLDs regardless its etiology.

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“…Oxidative stress can release zinc from zinc finger transcription factors, leading to loss of DNA binding activity. We found that chronic alcohol exposure inhibits hepatocyte nuclear factor-4α(HNF-4α) function without affecting its protein level, suggesting a zinc release from the protein which was then further validated by our group (Kang et al, 2008, 2009). Zinc deprivation also inactivated other zinc proteins, such as insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) (Kang et al, 2008).…”

Section: Macronutrients Micronutrients and Probiotics In Ald Dementioning

confidence: 54%

“…We found that chronic alcohol exposure inhibits hepatocyte nuclear factor-4α(HNF-4α) function without affecting its protein level, suggesting a zinc release from the protein which was then further validated by our group (Kang et al, 2008, 2009). Zinc deprivation also inactivated other zinc proteins, such as insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) (Kang et al, 2008). These results support the concept that oxidative stress with inactivation of zinc finger proteins is an important molecular mechanism in the development of ALD, and yet another reason to provide zinc supplementation in ALD (recommended dose 220 mg zinc sulfate = 50 mg elemental zinc/day).…”

Section: Macronutrients Micronutrients and Probiotics In Ald Dementioning

confidence: 54%

Alcoholic and non-alcoholic steatohepatitis

Neuman

French

et al. 2014

Experimental and Molecular Pathology

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This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

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Zinc Supplementation Enhances Hepatic Regeneration by Preserving Hepatocyte Nuclear Factor-4α in Mice Subjected to Long-Term Ethanol Administration

Cited by 35 publications

References 52 publications

Inactivation of hepatocyte nuclear factor-4α mediates alcohol-induced downregulation of intestinal tight junction proteins

Inactivation of hepatocyte nuclear factor-4α mediates alcohol-induced downregulation of intestinal tight junction proteins

Study of Serum Copper and Iron in Children with Chronic Liver Diseases

Alcoholic and non-alcoholic steatohepatitis

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