UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now well known that the addition and trimming of oligosaccharide side chains during post-translational modification play an important role in determining the fate of secretory, membrane, and lysosomal glycoproteins. Recent studies have suggested that trimming of oligosaccharide side chains also plays a role in the degradation of misfolded glycoproteins as a part of the quality control mechanism of the endoplasmic reticulum (ER). In this study, we examined the effect of several inhibitors of carbohydrate processing on the fate of the misfolded secretory protein alpha1 antitrypsin Z. Retention of this misfolded glycoprotein in the ER of liver cells in the classical form of alpha1 antitrypsin (alpha1-AT) deficiency is associated with severe liver injury and hepatocellular carcinoma and lack of its secretion is associated with destructive lung disease/emphysema. The results show marked alterations in the fate of alpha1 antitrypsin Z (alpha1-ATZ). Indeed, one glucosidase inhibitor, castanospermine (CST), and two mannosidase inhibitors, kifunensine (KIF) and deoxymannojirimycin (DMJ), mediate marked increases in secretion of alpha1-ATZ by distinct mechanisms. The effects of these inhibitors on secretion have interesting implications for our understanding of the quality control apparatus of the ER. These inhibitors may also constitute models for development of additional drugs for chemoprophylaxis of liver injury and emphysema in patients with alpha1-AT deficiency.
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PMID:Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha1 antitrypsin Z. 1063 1

Although there is evidence for specific subcellular morphological alterations in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), it is not clear whether these morphological changes are stereotypical or if they depend on the specific misfolded protein retained. This issue may be particularly important for mutant secretory protein alpha(1)-antitrypsin (alpha(1)AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with alpha(1)AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression and ER retention of mutant alpha(1)ATZ and in human liver from three alpha(1)AT-deficient patients. In addition to marked expansion and dilatation of ER, there was an intense autophagic response. Mutant alpha(1)ATZ molecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of alpha(1)ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTRDeltaF508, expression of mutant alpha(1)ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant alpha(1)ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of alpha(1)AT-deficient patients attempts to protect itself from injury and carcinogenesis.
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PMID:Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. 1105 93

The classical form of alpha 1-antitrypsin (alpha 1-AT) deficiency is associated with a mutant alpha 1-ATZ molecule that polymerizes in the endoplasmic reticulum (ER) of liver cells. A subgroup of individuals homozygous for the protease inhibitor (PI) Z allele develop chronic liver injury and are predisposed to hepatocellular carcinoma. In this study we evaluated the primary structure of alpha 1-AT in a family in which three affected members had severe liver disease associated with alpha 1-AT deficiency. We discovered that one sibling was a compound heterozygote with one PI Z allele and a second allele, the PI Z + saar allele, bearing the mutation that characterizes alpha 1-ATZ as well as the mutation that characterizes alpha 1-AT Saarbrucken (alpha 1-AT saar). The mutation in PI saar introduces a premature termination codon resulting in an alpha 1-AT protein truncated for 19 amino acids at its carboxyl terminus. Studies of a second sib with severe liver disease and other living family members did not reveal the presence of the alpha 1-AT saar mutation and therefore do not substantiate a role for this mutation in the liver disease phenotype of this family. However, studies of alpha 1-AT saar and alpha 1-ATZ + saar expressed in heterologous cells show that there is prolonged intracellular retention of these mutants even though they do not have polymerogenic properties. These results therefore have important implications for further understanding the fate of mutant alpha 1-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in alpha 1-AT deficiency.
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PMID:A naturally occurring nonpolymerogenic mutant of alpha 1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. 1142 40

Because retention of mutant alpha(1)-antitrypsin (alpha(1)-AT) Z in the endoplasmic reticulum (ER) is associated with liver disease in alpha(1)-AT-deficient individuals, the mechanism by which this aggregated glycoprotein is degraded has received considerable attention. In previous studies using stable transfected human fibroblast cell lines and a cell-free microsomal translocation system, we found evidence for involvement of the proteasome in degradation of alpha(1)-ATZ (Qu, D., Teckman, J. H., Omura, S., and Perlmutter, D. H. (1996) J. Biol. Chem. 271, 22791-22795). In more recent studies, Cabral et al. (Cabral, C. M., Choudhury, P., Liu, Y., and Sifers, R. N. (2000) J. Biol. Chem. 275, 25015-25022) found that degradation of alpha(1)-ATZ in a stable transfected murine hepatoma cell line was inhibited by tyrosine phosphatase inhibitors, but not by the proteasomal inhibitor lactacystin and concluded that the proteasome was only involved in ER degradation of alpha(1)-ATZ in nonhepatocytic cell types or in cell types with levels of alpha(1)-AT expression that are substantial lower than that which occurs in hepatocytes. To examine this important issue in further detail, in this study we established rat and murine hepatoma cell lines with constitutive and inducible expression of alpha(1)-ATZ. In each of these cell lines degradation of alpha(1)-ATZ was inhibited by lactacystin, MG132, epoxomicin, and clasto-lactacystin beta-lactone. Using the inducible expression system to regulate the relative level of alpha(1)-ATZ expression, we found that lactacystin had a similar inhibitory effect on degradation of alpha(1)-ATZ at high and low levels of alpha(1)-AT expression. Although there is substantial evidence that other mechanisms contribute to ER degradation of alpha(1)-ATZ, the data reported here indicate that the proteasome plays an important role in many cell types including hepatocytes.
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PMID:The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. 1157 74

Homozygous, PIZZ alpha(1)-antitrypsin (alpha(1)-AT) deficiency is associated with chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of mutant alpha(1)-anti-trypsin Z (alpha(1)-ATZ) protein retained in the endoplasmic reticulum (ER) of hepatocytes. However, the exact mechanism(s) by which retention of this aggregated mutant protein leads to cellular injury are still unknown. Previous studies have shown that retention of mutant alpha(1)-ATZ in the ER induces an intense autophagic response in hepatocytes. In this study, we present evidence that the autophagic response induced by ER retention of alpha(1)-ATZ also involves the mitochondria, with specific patterns of both mitochondrial autophagy and mitochondrial injury seen in cell culture models of alpha(1)-AT deficiency, in PiZ transgenic mouse liver, and in liver from alpha(1)-AT-deficient patients. Evidence for a unique pattern of caspase activation was also detected. Administration of cyclosporin A, an inhibitor of mitochondrial permeability transition, to PiZ mice was associated with a reduction in mitochondrial autophagy and injury and reduced mortality during experimental stress. These results provide evidence for the novel concept that mitochondrial damage and caspase activation play a role in the mechanism of liver cell injury in alpha(1)-AT deficiency and suggest the possibility of mechanism-based therapeutic interventions.
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PMID:Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. 1468 78

HIV caregivers face many challenges following initiation of ART. The development of jaundice is uncommon but worrisome. In this case, two distinct and contrasting episodes of jaundice were observed. In the first instance, isolated elevation of the indirect bilirubin without elevation of the alkaline phosphatase was noted. The normal PT and serum aminotransferase levels indicate the absence of intrinsic liver dysfunction. Elevations in the indirect bilirubin may result from either impaired uptake/conjugation or excess production. The latter, usually from acquired hemolysis, may be a complication of an occult NHL. A work-up for this AIDS-related malignancy was not initiated since the caregivers recognized jaundice as a complication of IDV, which inhibits UDP-glucuronyl transferase and produces a Gilbert's-like syndrome. Physicians can expect to encounter this syndrome even more frequently with ATV. Experienced patients given RTV-boosted ATV have experienced elevations of unconjugated hyper-bilirubinemia in up to 45 percent of cases in clinical trials. However, such elevations do not reflect liver dysfunction and symptomatic jaundice requiring dosage reduction that occurred infrequently (7 to 8 percent of study patients). Counseling patients about this syndrome may promote adherence and prevent self-directed interruptions of ATV that compromise efficacy. The second case of jaundice provides a more formidable diagnostic challenge. The triad of LFT abnormalities (mild elevation of aminotransferases, normal PT, and marked cholestatic jaundice) implies an acute process that is mildly toxic to hepatocytes without affecting their synthetic function. The subacute nature of the patient's cholestatic jaundice suggests either intrahepatic infiltrative disease of the liver or extrahepatic obstruction of the biliary tree, most likely due to the patient's relatively modest level of pain and lack of fever. Despite LFT abnormalities occurring 17 months after a switch in his ART, cumulative drug-related toxicities must still be considered. Ritonavir can produce significant elevations in the AST/ALT, especially with pre-existing chronic liver disease as with hepatitis C virus coinfection. The NRTIs can produce hepatic steatosis, a result of mitochondrial toxicity and impaired fatty acid oxidation. However, jaundice and cholestasis are not typical of the latter syndrome. With a negative contrast CT that excludes parenchymal liver disease, investigation of the biliary tree to assess the presence of AIDS-related cholangitis was the next step. Performing a sphincterotomy or stent placement, and obtaining brushings or biopsy specimens to determine the extent of extrahepatic obstruction may help define a pathogen and be life-saving. The negative results of the ERCP justify the final diagnostic step, a liver biopsy to evaluate microscopic infiltrative disease that might not have been detected on contrast abdominal CT. Examples might include granulomatous disease (MAC), fungal etiologies (histoplasmosis), carcinomatosis (lymphoma, hepatoma, cholangiocarcinoma), and microvascular disease (bacillary angiomatosis). The failure to observe granulomatous inflammation in the liver does not exclude MAC infection, as MAC may involve other peri-aortic or mesenteric lymph nodes. This form of IRIS is unlikely given the abdominal CT findings, lack of systemic complaints, and extended persistence of liver aminotransferases. The nonspecific results of the liver biopsy are a common outcome in advanced AIDS patients with elevated alkaline phosphatase levels. Despite not having identified a pathogen, the biopsy establishes chronic liver disease and prompts re-evaluation and change of treatment to NFV. The subsequent normalization of the patient's aminotransferase levels suggests a prior adverse effect of LPV/r in the setting of unexplained, chronic liver disease. Most importantly, this case highlights the importance of HIV caregivers to review ART for safety when noting chronic liver dysfunction. Patients need to be counseled to minimize acetaminophen use, to consume alcohol in moderation, and to avoid behavior with risk for hepatitis C. Finally, all HIV patients should receive appropriate vaccination against hepatitis A and B if serology shows lack of protective immunity.
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PMID:Clinical vignette in antiretroviral therapy: jaundice. 1498 14

Mutant alpha(1)-antitrypsin Z (alpha(1)-ATZ) protein, which has a tendency to form aggregated polymers as it accumulates within the endoplasmic reticulum of the liver cells, is associated with the development of chronic liver injury and hepatocellular carcinoma in hereditary alpha(1)-antitrypsin (alpha(1)-AT) deficiency. Previous studies have suggested that efficient intracellular degradation of alpha(1)-ATZ is correlated with protection from liver disease in alpha(1)-AT deficiency and that the ubiquitin-proteasome system accounts for a major route, but not the sole route, of alpha(1)-ATZ disposal. Yet another intracellular degradation system, autophagy, has also been implicated in the pathophysiology of alpha(1)-AT deficiency. To provide genetic evidence for autophagy-mediated disposal of alpha(1)-ATZ, here we used cell lines deleted for the Atg5 gene that is necessary for initiation of autophagy. In the absence of autophagy, the degradation of alpha(1)-ATZ was retarded, and the characteristic cellular inclusions of alpha(1)-ATZ accumulated. In wild-type cells, colocalization of the autophagosomal membrane marker GFP-LC3 and alpha(1)-ATZ was observed, and this colocalization was enhanced when clearance of autophagosomes was prevented by inhibiting fusion between autophagosome and lysosome. By using a transgenic mouse with liver-specific inducible expression of alpha(1)-ATZ mated to the GFP-LC3 mouse, we also found that expression of alpha(1)-ATZ in the liver in vivo is sufficient to induce autophagy. These data provide definitive evidence that autophagy can participate in the quality control/degradative pathway for alpha(1)-ATZ and suggest that autophagic degradation plays a fundamental role in preventing toxic accumulation of alpha(1)-ATZ.
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PMID:Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. 1636 39

Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. In addition to chronic liver inflammation and injury, it has a predilection to cause hepatocellular carcinoma later in life. The deficiency is caused by a mutant protein, ATZ, which is retained in the endoplasmic reticulum (ER) in a polymerized form rather than secreted into the blood in its monomeric form. The histologic hallmark of the disease is ATZ-containing globules in some, but not all, hepatocytes. Liver injury results from a gain-of-toxic function mechanism in which mutant ATZ retained in the ER initiates a series of pathologic events, but little is known about the mechanism by which this leads to carcinogenesis. Several recent observations from my laboratory have led to a novel hypothetical paradigm for carcinogenesis in AT deficiency in which globule-containing hepatocytes are "sick," relatively growth suppressed, but also elaborating trans-acting regenerative signals. These signals are received and transduced by globule-devoid hepatocytes, which, because they are younger and have a lesser load of accumulated ATZ, have a selective proliferative advantage. Chronic regeneration in the presence of tissue injury leads to adenomas and ultimately carcinomas. Aspects of this hypothetical paradigm may also explain the proclivity for hepatocarcinogenesis in other chronic liver diseases, including other genetic diseases, viral hepatitis, and nonalcoholic steatohepatitis.
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PMID:Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. 1686 11

Deficiency of circulating alpha-1-antitrypsin (AAT) is the most widely recognized abnormality of a proteinase inhibitor that causes lung disease. AAT-deficiency is caused by mutations of the AAT gene that lead to AAT protein retention in the endoplasmic reticulum (ER). Moreover, the mutant AAT accumulated in the ER predisposes the homozygote to severe liver injuries, such as neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Despite the fact that mutant AAT protein is subject to ER-associated degradation (ERAD), yeast genetic studies have determined that the ubiquitination machinery, Hrd1/Der3p-cue1p-Ubc7/6p, which plays a prominent role in ERAD, is not involved in degradation of mutant AAT. Here we report that gp78, a ubiquitin ligase (E3) pairing with mammalian Ubc7 for ERAD, ubiquitinates and facilitates degradation of ATZ, the classic deficiency variant of AAT having a Z mutation (Glu 342 Lys). Unexpectedly, gp78 over-expression also significantly increases ATZ solubility. p97/VCP, an AAA ATPase essential for retrotranslocation of misfolded proteins from the ER during ERAD, is involved in gp78-mediated degradation of ATZ. Surprisingly, unlike other ERAD substrates that cause ER stress leading to apoptosis when accumulated in the ER, ATZ, in fact, increases cell proliferation when over-expressed in cells. This effect can be partially inhibited by gp78 over-expression. These data indicate that gp78 assumes multiple unique quality control roles over ATZ, including the facilitation of degradation and inhibition of aggregation of ATZ.
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PMID:Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of alpha-1-antitrypsin. 1697 36

Homozygous (PIZZ) alpha-1-antitrypsin (alpha(1)-AT) deficiency is associated with the development of liver damage in children as well as chronic liver injury and hepatocellular carcinoma in adults. The alpha(1)-AT mutant Z gene encodes a mutant protein that accumulates in the endoplasmic reticulum of hepatocytes rather than being secreted appropriately into serum. Liver injury is caused by the accumulation of alpha(1)-AT mutant Z protein in hepatocytes, which triggers downstream intracellular injury pathways. However, development of clinical liver disease among PIZZ homozygotes is highly variable, suggesting other genetic or environmental factors contribute to liver injury. In this study, we tested whether nonsteroidal anti-inflammatory drugs (NSAIDs) could be a comorbid factor in the development of liver injury in alpha(1)-AT deficiency using the PiZ mouse. This mouse model is transgenic for the mutant Z allele of the human alpha(1)-AT gene, in which alpha(1)-ATZ expression is regulated by the human promoter regulatory sequences. Our results showed that administration of indomethacin to PiZ mice resulted in increased hepatic injury, indicated by increased hepatocellular proliferation and increased activation of caspase 9. This indomethacin-induced injury was associated with activation of IL-6-STAT3 signaling, increased expression of alpha(1)-AT mRNA, and greater accumulation of mutant polymerized alpha(1)-ATZ protein in livers of indomethacin-treated PiZ mice compared to vehicle-treated PiZ animals. In conclusion, environmental factors, such as exogenous medication administration, can significantly potentiate the liver injury associated with alpha(1)-ATZ hepatic accumulation; NSAIDs may be especially injurious to patients with alpha(1)-AT deficiency, possibly by increasing the expression and accumulation of the hepatotoxic mutant protein.
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PMID:Indomethacin increases liver damage in a murine model of liver injury from alpha-1-antitrypsin deficiency. 1700 46

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