The liver in adolescents with α-antitrypsin deficiency

Sveger, Tomas; Eriksson, Sten

doi:10.1002/hep.1840220221

Cited by 104 publications

(90 citation statements)

References 23 publications

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“…Prospective nationwide screening studies carried out in Sweden have confirmed that only ϳ10% of this population develops clinically significant liver disease (21,22). Using a genetic complementation approach, we found that there is less efficient ER degradation of ␣1-ATZ in cells from some ␣1-AT-deficient individuals who are susceptible to liver disease (16) and, therein, that these individuals have a lesser inherent capacity to respond to, and/or protect themselves from, the hepatotoxic circumstances posed by ER retention of mutant ␣1-ATZ.…”

Section: Discussionmentioning

confidence: 99%

A Naturally Occurring Nonpolymerogenic Mutant of α1-Antitrypsin Characterized by Prolonged Retention in the Endoplasmic Reticulum

Schmidt

Teckman

et al. 2001

Journal of Biological Chemistry

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The classical form of ␣1-antitrypsin (␣1-AT) deficiency is associated with a mutant ␣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 ␣1-AT in a family in which three affected members had severe liver disease associated with ␣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 ␣1-ATZ as well as the mutation that characterizes ␣1-AT Saarbrucken (␣1-AT saar). The mutation in PI saar introduces a premature termination codon resulting in an ␣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 ␣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 ␣1-AT saar and ␣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 ␣1-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in ␣1-AT deficiency.

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Section: Discussionmentioning

confidence: 99%

A Naturally Occurring Nonpolymerogenic Mutant of α1-Antitrypsin Characterized by Prolonged Retention in the Endoplasmic Reticulum

Schmidt

Teckman

et al. 2001

Journal of Biological Chemistry

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“…Some present in liver failure and require liver transplantation in the first several years of life whereas others do not manifest any clinical signs of liver disease for many years. A prospective nationwide screening study in Sweden has shown that 80-90% of PIZZ individuals identified prospectively have no clinical evidence of liver disease by 18 years of age, their age at the time of the last report on this population (11). Although some of these patients may have subclinical liver injury as evidenced by the fact that cirrhosis and hepatocellular carcinoma can be found incidentally at autopsy in PIZZ individuals who have died of other causes (12), the overwhelming clinical experience with this disease indicates that there is a high degree of genotype-phenotype variation in the effect of ␣1-AT deficiency on the development of liver disease and a number of PIZZ individuals are relatively ''protected'' from liver disease or have very slowly progressing liver disease.…”

mentioning

confidence: 99%

Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency

Burrows

Willis

Perlmutter

2000

Proc. Natl. Acad. Sci. U.S.A.

420

268

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In ␣1-AT deficiency, a misfolded but functionally active mutant ␣1-ATZ (␣1-ATZ) molecule is retained in the endoplasmic reticulum of liver cells rather than secreted into the blood and body fluids. Emphysema is thought to be caused by the lack of circulating ␣1-AT to inhibit neutrophil elastase in the lung. Liver injury is thought to be caused by the hepatotoxic effects of the retained ␣1-ATZ. In this study, we show that several ''chemical chaperones,'' which have been shown to reverse the cellular mislocalization or misfolding of other mutant plasma membrane, nuclear, and cytoplasmic proteins, mediate increased secretion of ␣1-ATZ. In particular, 4-phenylbutyric acid (PBA) mediated a marked increase in secretion of functionally active ␣1-ATZ in a model cell culture system. Moreover, oral administration of PBA was well tolerated by PiZ mice (transgenic for the human ␣1-ATZ gene) and consistently mediated an increase in blood levels of human ␣1-AT reaching 20 -50% of the levels present in PiM mice and normal humans. Because clinical studies have suggested that only partial correction is needed for prevention of both liver and lung injury in ␣1-AT deficiency and PBA has been used safely in humans, it constitutes an excellent candidate for chemoprophylaxis of target organ injury in ␣1-AT deficiency.

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“…One interesting observation, arising from unbiased nationwide screening studies of ␣ 1 -AT deficiency in Sweden, indicates that only 10 -15% of deficient individuals develop clinically significant liver disease (8,9). In previous studies we tested the hypothesis that this subgroup of deficient individuals is susceptible to liver injury by virtue of additional unlinked genetic traits or environmental factors that delay degradation of the mutant ␣ 1 -ATZ molecule after it is retained in the ER (10).…”

mentioning

confidence: 99%

The Proteasome Participates in Degradation of Mutant α1-Antitrypsin Z in the Endoplasmic Reticulum of Hepatoma-derived Hepatocytes

Teckman¹,

Burrows²,

Hidvegi³

et al. 2001

Journal of Biological Chemistry

132

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Because retention of mutant ␣ 1 -antitrypsin (␣ 1 -AT) Z in the endoplasmic reticulum (ER) is associated with liver disease in ␣ 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 Chem. 275, 25015-25022) found that degradation of ␣ 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 ␣ 1 -ATZ in nonhepatocytic cell types or in cell types with levels of ␣ 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 ␣ 1 -ATZ. In each of these cell lines degradation of ␣ 1 -ATZ was inhibited by lactacystin, MG132, epoxomicin, and clasto-lactacystin ␤-lactone. Using the inducible expression system to regulate the relative level of ␣ 1 -ATZ expression, we found that lactacystin had a similar inhibitory effect on degradation of ␣ 1 -ATZ at high and low levels of ␣ 1 -AT expression. Although there is substantial evidence that other mechanisms contribute to ER degradation of ␣ 1 -ATZ, the data reported here indicate that the proteasome plays an important role in many cell types including hepatocytes.The classical and most common form of ␣ 1 -antitrypsin (␣ 1 -AT) 1 deficiency is a relatively unique genetic disease in that it is associated with injury to one tissue, pulmonary emphysema, by a loss-of-function mechanism and injury to another tissue, chronic hepatitis/hepatocellular carcinoma, by a gain-of-function mechanism. Many studies have provided evidence that emphysema results from lack of the anti-elastase activity of ␣ 1 -AT in the lung (reviewed in Refs. 1 and 2). Liver disease is due to toxic effects of aggregated ␣ 1 -ATZ retained in the ER of liver parenchymal cells. The gain-of-function mechanism is most clearly demonstrated by experiments in mice transgenic for human ␣ 1 -ATZ. These mice develop liver injury and hepatocellular carcinoma despite the fact that they have their own endogenous anti-elastases (3-5).The mutant Z allele of ␣ 1 -AT is characterized by a single nucleotide substitution, which results in the replacement of glutamate 342 by a bulky lysine residue (1, 2). The studies of Carrell and Lomas (6, 7) have shown that this substitution renders the ␣ 1 -AT molecule more susceptible to polymerization and that highly ordered aggregates accumulate in the ER of liver cells.One interesting observation, arising from unbiased nationwide screening studies of ␣ 1 -AT deficiency in Sweden, indicates that only 10 -15% of deficient individuals develop clinically significant liver disease (8,9...

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The liver in adolescents with α-antitrypsin deficiency

Cited by 104 publications

References 23 publications

A Naturally Occurring Nonpolymerogenic Mutant of α1-Antitrypsin Characterized by Prolonged Retention in the Endoplasmic Reticulum

A Naturally Occurring Nonpolymerogenic Mutant of α1-Antitrypsin Characterized by Prolonged Retention in the Endoplasmic Reticulum

Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency

The Proteasome Participates in Degradation of Mutant α1-Antitrypsin Z in the Endoplasmic Reticulum of Hepatoma-derived Hepatocytes

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