Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death

Vogel, Arndt; Berg, Inge E.T. van den; Al‐Dhalimy, Muhsen; Groopman, John D.; Ou, Ching Nan; Ryabinina, Olga P.; Iordanov, Mihail S.; Finegold, Milton J.; Grompe, Markus

doi:10.1002/hep.20077

Cited by 64 publications

(82 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The protective effect of sublethal doses of anti-Fas antibodies toward the lethal effects of higher doses of such antibodies has also been recognized (58). More recently the enhanced resistance of the chronically injured liver to subsequent damage has been substantiated in an experimental model of hereditary tyrosinemia (fumarylacetoacetate hydrolase-deficient, FAHϪ/Ϫ, mice) (48). Pre-existing chronic liver damage in these mice resulted in protection from ethanol, acetaminophen, and Fas-mediated liver injury and apoptosis (48).…”

Section: Discussionmentioning

confidence: 99%

“…More recently the enhanced resistance of the chronically injured liver to subsequent damage has been substantiated in an experimental model of hereditary tyrosinemia (fumarylacetoacetate hydrolase-deficient, FAHϪ/Ϫ, mice) (48). Pre-existing chronic liver damage in these mice resulted in protection from ethanol, acetaminophen, and Fas-mediated liver injury and apoptosis (48). Interestingly, similar to what has been observed in the apoptosis-resistant FAHϪ/Ϫ mice (48), AR null mice displayed blunted activation of the apoptosis-associated kinase JNK upon Fas ligation.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon is widely recognized in the field of liver surgery and transplantation, where acute cell stress or injury induced by ischemic preconditioning can protect against subsequent reperfusion injury (49,50). More recently, the protective effects of a preexisting chronic liver disease have also been identified in a murine model of hereditary tyrosinemia (48). Considering this hypothesis, we went on to examine whether ARϪ/Ϫ mice displayed signs of chronic liver damage that might precondition hepatocytes against cell death.…”

Section: Expression Of Egf-r Ligands In Mouse Liver After the Adminismentioning

confidence: 99%

See 2 more Smart Citations

Novel Role for Amphiregulin in Protection from Liver Injury

Berasain

Garcı́a-Trevijano

Castillo

et al. 2005

Journal of Biological Chemistry

119

123

View full text Add to dashboard Cite

Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor ␣, heparinbinding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Expression Of Egf-r Ligands In Mouse Liver After the Adminismentioning

confidence: 99%

See 1 more Smart Citation

Novel Role for Amphiregulin in Protection from Liver Injury

Berasain

Garcı́a-Trevijano

Castillo

et al. 2005

Journal of Biological Chemistry

119

123

View full text Add to dashboard Cite

show abstract

“…5) may be involved in the mechanism of liver injury and hepatocarcinogenesis in the fumarylacetoacetate hydrolase-deficient (FAH) mouse model of tyrosinemia. 43 In these studies, the liver of the FAH mouse was found to contain hepatocytes that were damaged but not dead. In fact, these cells were found to be resistant to cell death and, therein, prone to carcinogenesis.…”

Section: Hypothetical Model For Hepatocellular Carcinoma In ␣1at Defimentioning

confidence: 99%

“…However, they share the property of being TUNEL-negative, and upregulation of antiapoptotic heat shock proteins has also been implicated in the block in their cell death. 43 There is also evidence in the FAH mouse for chronic stimulation in "trans" of hepatocytes that are not damaged and have a selective proliferative advantage. According to the paradigm we are proposing here, these hepatocytes correspond to the globule-devoid hepatocytes in the PiZ mouse liver.…”

Section: Hypothetical Model For Hepatocellular Carcinoma In ␣1at Defimentioning

confidence: 99%

Alpha-1-antitrypsin deficiency: A new paradigm for hepatocellular carcinoma in genetic liver disease

2005

View full text Add to dashboard Cite

Liver disease in alpha-1-antitrypsin (␣1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial-and ER-caspase activation, and nuclear factor kappaB (NF B) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of ␣1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective T he classic form of alpha-1-antitrypsin (␣1AT) deficiency, associated with homozygosity for the ␣1ATZ allele, is the most common genetic cause of liver disease in children. It also causes chronic liver injury and hepatocellular carcinoma in adults. 1 Moreover, the predilection for hepatocellular carcinoma in homozygotes for the Z allele is significantly greater than that attributable to cirrhosis alone. 1 The histopathological hallmark of the disease is intracellular globules in hepatocytes that stain positively with periodic acid-Schiff (PAS) after treatment with diastase, the so-called PAS-positive/ diastase-resistant globules. Early studies showed that these globules represent the mutant glycoprotein, ␣1ATZ, retained in the rough endoplasmic reticulum (ER) of liver cells (reviewed in Perlmutter 2 ). Although considerable discussion of these globules is found in the literature as well as investigation of their origin, relatively limited discussion, or investigation, has taken place, regarding the curious fact that many hepatocytes in these patients do not have globules (Fig. 1). Studies of the Z#2 mouse model, generated by using a human ␣1ATZ genomic fragment as transgene, 3 have shown that these globuledevoid cells occupy an increasing proportion of the liver as the animal ages and ultimately become the site of adenomas and carcinomas. 4 In more recent studies using the PiZ mouse model, another transgenic mouse created with a human ␣1ATZ genomic fragment, 5 we have shown that there is increased proliferation of these globule-devoid hepatocytes at a rate that is directly proportional to the number of globule-containing hepatocytes. 6

show abstract

Temporal Dynamics of Metabolic Acquisition in Grafted Engineered Human Liver Tissue

et al. 2022

View full text Add to dashboard Cite

Liver disease affects millions globally, and end‐stage liver failure is only cured by organ transplant. Unfortunately, there is a growing shortage of donor organs as well as inequitable access to transplants across populations. Engineered liver tissue grafts that supplement or replace native organ function can address this challenge. While engineered liver tissues have been successfully engrafted previously, the extent to which these tissues express human liver metabolic genes and proteins remains unknown. Here, it is built engineered human liver tissues and characterized their engraftment, expansion, and metabolic phenotype at sequential stages post‐implantation by RNA sequencing, histology, and host serology. Expression of metabolic genes is observed at weeks 1–2, followed by the cellular organization into hepatic cords by weeks 4–9.5. Furthermore, grafted engineered tissues exhibited progressive spatially restricted expression of critical functional proteins known to be zonated in the native human liver. This is the first report of engineered human liver tissue zonation after implantation in vivo, which can have important translational implications for this field.

show abstract

Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death

Cited by 64 publications

References 44 publications

Novel Role for Amphiregulin in Protection from Liver Injury

Novel Role for Amphiregulin in Protection from Liver Injury

Alpha-1-antitrypsin deficiency: A new paradigm for hepatocellular carcinoma in genetic liver disease

Temporal Dynamics of Metabolic Acquisition in Grafted Engineered Human Liver Tissue

Contact Info

Product

Resources

About