Chronic ethanol administration to rats decreases receptor-operated mobilization of intracellular ionic calcium in cultured hepatocytes and inhibits 1,4,5-inositol trisphosphate production: relevance to impaired liver regeneration.

Zhang, B H; Hornsfield, B P; Farrell, Geoffrey C.

doi:10.1172/jci118907

Cited by 35 publications

(27 citation statements)

References 50 publications

(50 reference statements)

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“…Hepatocyte proliferation has been shown to be impaired in alcohol-induced liver disease 50 and more recently in rodents [51][52][53] and humans with fatty liver. 52 The imbalance between enhanced proliferative drive from HCV and impaired primary hepatocyte proliferation from steatosis and other factors may lead to default proliferation of bipotential hepatic progenitor cells (HPC) and a bile ductular reaction.…”

Section: Potential Pathogenic Roles Of Steatosis and Obesity In Hepatmentioning

confidence: 99%

Steatosis: Co-factor in Other Liver Diseases *

2005

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The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol-and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis. (HEPATOLOGY 2005;42:5-13.)

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Section: Potential Pathogenic Roles Of Steatosis and Obesity In Hepatmentioning

confidence: 99%

Steatosis: Co-factor in Other Liver Diseases *

2005

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“…In addition, impaired liver regeneration is also an important mechanism contributing to the pathogenesis of alcoholic liver disease. Chronic ethanol consumption has been shown to inhibit liver regeneration after partial hepatectomy in rodents (Diehl et al, 1988;Koteish et al, 2002;Orrego et al, 1981;Wands et al, 1979;Zhang et al, 1996). Clinical studies have showed that proliferating hepatocytes in alcoholic liver diseases (not cirrhotic) or alcohol plus HCV-mediate diseases (not cirrhotic) were lower than in viral liver damage (not cirrhotic), suggesting that liver regeneration is also suppressed in noncirrhotic patients with alcoholic liver diseases (Cardin et al, 2002;Farinati et al, 1996;Farinati et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Horiguchi¹,

Ishac²,

Gao³

2007

Alcohol

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Liver regeneration is suppressed in alcoholic patients; however, the underlying mechanisms are not fully understood. We examined liver regeneration and STAT3 activation (an important signal for liver regeneration) in cirrhotic livers from alcoholics, HCV infection, and alcoholic plus HCV infection. Liver regeneration and STAT3 activation were determined by immunohistochemistry analysis of Ki67 and STAT3 phosphorylation, respectively, in 20 alcoholic cirrhosis, 13 HCV cirrhosis, 13 alcoholic+HCV cirrhosis. Alcoholic or alcoholic plus HCV cirrhotic livers had significantly lower Ki67 + and pSTAT3 + hepatocytes and bile duct cells than HCV cirrhotic livers. The pSTAT3 positive staining did not correlate with liver injury (elevation of serum levels of aspartate transaminase (ALT) and alkaline phosphatase (ALP) but correlated positively with cell proliferation (Ki67 positive staining). In conclusion: Liver regeneration is suppressed in alcoholic cirrhotic livers, which may be partly due to decreased STAT3 activation.

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“…3 Conversely, gene transfer-mediated overexpression of BI-1 protects against apoptosis induced by ER stress and IR (10,11,13). In this regard, the ER may participate in the initiation of liver regeneration by releasing stored Ca 2+ (14). Indeed, in many types of cells, including fibroblasts, thymocytes, and epithelial tumor cell lines, intracellular Ca 2+ is essential for the transition from resting to proliferative state (15 (12).…”

Section: Introductionmentioning

confidence: 99%

Mice Lacking bi-1 Gene Show Accelerated Liver Regeneration

et al. 2007

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The liver has enormous regenerative capacity such that, after partial hepatectomy, hepatocytes rapidly replicate to restore liver mass, thus providing a context for studying in vivo mechanisms of cell growth regulation. Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death. Interestingly, the BI-1 protein has been shown to regulate Ca 2+ handling by the ER similar to antiapoptotic Bcl-2 family proteins. Effects on cell cycle entry by Bcl-2 family proteins have been described, prompting us to explore whether bi-1-deficient mice display alterations in the in vivo regulation of cell cycle entry using a model of liver regeneration. Accordingly, we compared bi-1 +/+ and bi-1 À/À mice subjected to partial hepatectomy with respect to the kinetics of liver regeneration and molecular events associated with hepatocyte proliferation. We found that bi-1 deficiency accelerates liver regeneration after partial hepatectomy. Regenerating hepatocytes in bi-1 À/À mice enter cell cycle faster, as documented by more rapid incorporation of deoxynucleotides, associated with earlier increases in cyclin D1, cyclin D3, cyclin-dependent kinase (Cdk) 2, and Cdk4 protein levels, more rapid hyperphosphorylation of retinoblastoma protein, and faster degradation of p27 Kip1. Dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1), a substrate of the Ca 2+ -sensitive phosphatase calcineurin, were also accelerated following partial hepatectomy in BI-1-deficient hepatocytes. These findings therefore reveal additional similarities between BI-1 and Bcl-2 family proteins, showing a role for BI-1 in regulating cell proliferation in vivo, in addition to its previously described actions as a regulator of cell survival.

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Chronic ethanol administration to rats decreases receptor-operated mobilization of intracellular ionic calcium in cultured hepatocytes and inhibits 1,4,5-inositol trisphosphate production: relevance to impaired liver regeneration.

Cited by 35 publications

References 50 publications

Steatosis: Co-factor in Other Liver Diseases *

Steatosis: Co-factor in Other Liver Diseases *

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Mice Lacking bi-1 Gene Show Accelerated Liver Regeneration

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