Liver apoptosis

doi:10.1016/S0168-8278(97)80491-6

Journal of Hepatology

Volume 26, Supplement 2, 1997, Pages 1-11

https://doi.org/10.1016/S0168-8278(97)80491-6 Get rights and content

Abstract

Apoptosis, also called programmed cell death, is a peculiar form of cell death different from cell necrosis in many morphological and biochemical aspects. Like mitosis or differentiation, apoptosis is a normal cell phenomenon which depends on the expression of genes capable of inducing or inhibiting this type of cell destruction. But apoptosis can also be triggered by many external factors and has been described in many diseases. The very different conditions where programmed cell death occurs suggest that the mechanisms leading to the activation of apoptosis-controlling genes are variable. As in other cells, apoptosis occurs in the liver cells, first in the normal state during liver development and then in the adult liver, respectively for liver organogenesis and the renewal of hepatocytes. But apoptosis is also present in various viral, immunological, malignant or drug-induced human liver diseases. In addition, in the animal, hepatocyte apoptosis can be triggered either in vivo or in vitro by many toxic agents. In contrast to other cells, the mechanisms leading to liver cell apoptosis remain poorly investigated. However, two proteins could play an important role in this field, the fas/apo-1 protein present at the surface of hepatocytes and the bcl-2 protein localized in biliary cells. Analysis of the genes controlling the expression of these two proteins could provide essential information on the mechanisms of liver apoptosis.

References (117)

JFR Kerr
An electron microscopy study of liver cell necrosis due to albitocin
Pathology
(1970)
HM Ellis et al.
Genetic control of programmed cell death in the nematode C. elegans
Cell
(1986)
GT Williams et al.
Apoptosis: final control point in cell biology
Trends Cell Biol
(1992)
GT Williams et al.
Molecular regulation of apoptosis: genetic controls on cell death
Cell
(1993)
B Grasl-Kraupp et al.
In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note
Hepatology
(1995)
A Benedetti et al.
Preferential distribution of apoptotic bodies in acinar zone 3 of normal human and rat liver
J Hepatol
(1988)
MJ Arends et al.
Apoptosis: mechanisms and roles in pathology
Int Rev Exp Pathol
(1991)
SJ Martin
Apoptosis: suicide, execution or murder?
Trends Cell Biol
(1993)
MC Peitsch et al.
The apoptosis endonucleases: cleaning up after cell death?
Trends Cell Biol
(1994)
T Patel et al.
Apoptosis and hepatobiliary disease
Hepatology
(1995)

L Fesus et al.

Induction and activation of tissue transglutaminase during programmed cell death

Febs Lett

(1987)

SJ Martin et al.

Protease activation during apoptosis: death by a thousand cuts?

Cell

(1995)

M Piacentini et al.

In vivo and in vitro induction of “tissue” transglutaminase in rat hepatocytes by retinoic acid

Biochim Biophys Acta

(1992)

DJ McConkey et al.

Signal transduction pathways to apoptosis

Trends Cell Biol

(1994)

R Ni et al.

Fas-mediated apoptosis in primary cultured mouse hepatocytes

Exp Cell Res

(1994)

L Fesus et al.

Apoptotic hepatocytes become insoluble in detergents and chaotropic agents as a result of transglutaminase action

Febs Lett

(1989)

J Savill et al.

Phagocyte recognition of cells undergoing apoptosis

Immunol Today

(1993)

L Dini et al.

The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor

Febs Lett

(1992)

SJ Martin et al.

Dicing with death: dissecting the components of the apoptosis machinery

TIBS

(1994)

DM Hockenbery et al.

Bcl-2 functions in an antioxidant pathway to prevent apoptosis

Cell

(1993)

E Mita et al.

Role of fas ligand in apoptosis induced by hepatitis C virus infection

Biochem Biophys Res Commun

(1994)

JFR Kerr et al.

The nature of piecemeal necrosis in chronic active hepatitis

Lancet

(1979)

LM Helvering et al.

Expression of TRPM-2 during involution and regeneration of the rat liver

Cancer Lett

(1993)

D Bernuau et al.

Ultra-structural lesions of bile ducts in primary biliary cirrhosis. A comparison with the lesions observed in graft versus host disease

Hum Pathol

(1981)

GS Baroni et al.

Chronic ethanol feeding increases apoptosis and cell proliferation in rat liver

J Hepatol

(1994)

W Bursch et al.

Cell death by apoptosis and its protective role against disease

Trends Pharmacol Sci

(1992)

A Medline et al.

Ultrastructural features in galactosamine-induced hepatitis

Exp Mol Pathol

(1970)

TP King et al.

Autophagy and apoptosis in liver during the prehaemolytic phase of chronic copper poisoning in sheep

J Comp Pathol

(1979)

Y Kaneko et al.

Apoptosis and p53 protein expression in human hepatoma cells induced by etoposide, mitomycin C and thapsigargin

Intern Hepatol Commun

(1994)

JFR Kerr et al.

Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics

Br J Cancer

(1972)

C Biava et al.

Electron microscopic observations on Councilman-like acidophilic bodies and other forms of acidophilic changes in human liver cells

Am J Pathol

(1965)

FM Klion et al.

The ultrastucture of acidophilic “Councilman-like” bodies in the liver

Am J Pathol

(1966)

W Bursch et al.

Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats

Carcinogenesis

(1990)

H Popper

Y Gavrieli et al.

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

J Cell Biol

(1992)

JH Wijsman et al.

A new method to detect apoptosis in paraffin section: in situ end-labeling of fragmented DNA

J Histochem Cytochem

(1993)

JR Hully et al.

Induction of apoptosis in the murine liver with recombinant human activin A

Hepatology

(1994)

RD Goldin et al.

Apoptotic bodies in a murine model of alcoholic liver disease: reversibility of ethanol-induced changes

J Pathol

(1993)

N Arber et al.

The streaming liver. II. Hepatocyte life history

Liver

(1988)

JC Barrett et al.

RJ Scothorne et al.

The streaming liver: a slow, divided flow

Hepatology

(1986)

J Searle et al.

The significance of cell death by apoptosis in hepatobiliary disease

J Gastroenterol Hepatol

(1987)

A Columbano et al.

Occurrence of cell death (apoptosis) during the involution of liver hyperplasia

Lab Invest

(1985)

T Terada et al.

Detection of apoptosis and expression of apoptosis-related proteins during human intrahepatic bile duct development

Am J Pathol

(1995)

AH Wyllie

Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

Nature

(1980)

AH Wyllie et al.

Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis

J Pathol

(1984)

MJ McCabe et al.

Calcium-dependent cell death. Role of the endonuclease, protein kinase C, and chromatin conformation

An NY Acad Sci

(1992)

SD Ray et al.

Ca²⁺ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen

FASEB J

(1993)

F Oberhammer et al.

Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation

EMBO J

(1993)

MM Compton

A biochemical hallmark of apoptosis: internucleosomal degradation of the genome

Cancer Metast Rev

(1992)

Cited by (110)

Insulin resistance enhances binge ethanol-induced liver injury through promoting oxidative stress and up-regulation CYP2E1
2022, Life Sciences
Citation Excerpt :
The present study confirmed that IR could significantly sensitize the liver injury and inflammation response induced by ethanol. Apoptosis as one kind of cell deaths is characterized by special morphological and biochemical features such as apoptotic body [64]. It has been described that apoptosis cells were found in liver in the ALD model, and there is a significant correlation between apoptosis and liver injury [13].
Alcoholic liver disease (ALD) has caused a serious burden on public and personal health in crowd with ethanol abuse. The effects of insulin resistance (IR) on ALD and the mechanisms underlying these responses are still not well understood. In this study, we investigated the changes of liver injury, inflammation, apoptosis, mitochondrial dysfunction and CYP2E1 changes in liver of mice exposed to ethanol with IR or not. We found IR increased the sensitivity of liver injury in mice exposed to ethanol, manifested as the increase serum activities of AST and ALT, the accumulation of triglycerides, the deterioration of liver pathology and increase of inflammatory factors. IR also exacerbated apoptosis and mitochondrial dysfunction in liver of mice exposed to ethanol. The increase of oxidative stress and the decrease of antioxidant defense ability might be responsible for the sensitizing effects of IR on ethanol-induced liver injury, supported by the increase of MDA levels and the decline of GSH/GSSG, the inactivation of antioxidant enzymes SOD, GR through the inhibition of Nrf-2 pathway. The activation of CYP2E1 might be also involved in the sensitizing effects of IR on ethanol induced liver injury in mice. These results demonstrated that IR exhibited a significant pro-oxidative and pro-apoptosis effects to aggravate alcoholic liver injury. Our study helped us to better understand the sensitive role of IR on ALD and suggested that alcohol intake may be more harmful for people with IR.
Free fatty acid-induced miR-181a-5p stimulates apoptosis by targeting XIAP and Bcl2 in hepatic cells
2022, Life Sciences
Citation Excerpt :
Like other cells, apoptosis normally occurs in liver during development and in the renewal of hepatocytes. However, apoptosis can also be initiated in various other conditions, such as, viral infections, immunological, malignant and drug-induced liver disease [6]. Cytokeratin-18 fragments produced by caspase-3 were found in the NASH patients indicating enhanced apoptosis in these patients [7,8].
Non-alcoholic fatty liver disease is one of the major health concerns in the World. The dietary free fatty acids (FFAs) affect the metabolic status of the hepatocytes by modulating cellular pathways. In this study, we showed that free fatty acids stimulate apoptosis by upregulating miR-181a-5p expression, which in turn targets XIAP and Bcl2.
Huh7 cells were incubated with FFAs for 72 h and the expression of XIAP, Bcl2, bax, pAkt, Akt, PTEN and β-actin were determined by Western blots, and miR-181a-5p expression was determined using real-time RT-PCR. The Huh7 cells were transfected with either miR-181a-5p pre-miRs or anti-miR-181a-5p and the regulation of apoptosis and proliferation was studied. Three groups of C57BL/6 mice (n = 6 per group) were fed with standard diet, CSAA or CDAA diet for 6, 18, 32 and 54 weeks. Total protein and RNA were isolated from the liver tissues and used for Western blots and real-time RT-PCR respectively.
FFAs inhibited Akt phosphorylation, expression of XIAP and Bcl2, while upregulating the expression of PTEN, bax, and miR-181a-5p in Huh7 cells. Similar results were observed when the Huh7 cells were transfected with miR-181a-5p premiRs, while these changes were reversed in anti-miR-181a-5p-transfected, FFA-treated Huh7 cells. The CDAA-fed mice showed a significant inhibition of Akt phosphorylation, XIAP and Bcl2, whereas PTEN and bax expression were upregulated. The expression of miR-181a-5p was also significantly higher in CDAA-fed mice.
These findings showed that free fatty acids induced apoptosis via upregulating miR-181a-5p in hepatic cells.
The intrinsic apoptotic pathway lies upstream of oxidative stress in multiple organs
2020, Free Radical Biology and Medicine
Citation Excerpt :
However, increased generation of RS and/or reduced antioxidant capacity can give rise to oxidative stress and subsequently damages proteins, lipids and DNA. BAX is a pro-apoptotic protein involved in the intrinsic apoptotic pathway in a wide variety of tissues, including the brain, heart, liver, and kidney [18–21]. Insertion of BAX into the outer mitochondrial membrane triggers the release of cytochrome c from the mitochondrial intermembrane space into the cytosol where it induces formation of the apoptosome and subsequent activation of executioner caspases such as caspase-3 (CASP3) [22].
Oxidative stress increases with age in multiple organ systems and is implicated in the development of age-related pathologies in them. Studies from our laboratory show that the intrinsic pathway proapoptotic proteins BAX and caspase-3 (CASP3) lie upstream of mitochondrial production of oxidative stress-inducing reactive species (RS) such as reactive oxygen and reactive nitrogen species (ROS and RNS) in apoptotic and nonapoptotic neurons in cell culture. Our objective in this study was to determine if these findings could be generalized to the development of oxidative stress in nonneuronal tissues in vivo. We first investigated the effect of genetic deletion of Bax on DNA damage in the liver, heart and kidneys of female mice of increasing ages (5, 14, 22 months). The organs of the aged mice showed increased oxidative DNA strand breaks compared to young animals (5 month). Ablation of Bax greatly reduced this damage. We next assessed lipid peroxidation, DNA oxidation, and protein tyrosine nitration to determine whether Casp3 deletion reduces oxidative stress in the hearts, livers, and kidneys of 12-month-old female mice. Lipid peroxides and 8-hydroxy-2’-deoxyguanosine (8-OHdG) levels were much lower in organs from mice with depleted Casp3 than in those of wild type animals. Nitration of protein tyrosine residues, caused by RNS, was also significantly suppressed in the tissues of Casp3 null mice compared to those in wild type mice. Our findings indicate that BAX and CASP3 have a vital role in the generation of oxidative stress in organs of aged mice.
Apoptotic gene expression profiles and DNA damage levels in rat liver treated with perfluorooctane sulfonate and protective role of curcumin
2017, International Journal of Biological Macromolecules
Perfluorinated compounds (PFC_s) such as PFOS and PFOA, are xenobiotics that can be detected worldwide in the environment and humans. PFOS (C₈F₁₇SO₃⁻) is a fluorinated organic compound has been used for decades in industrial and commercial products. We investigated the genotoxic and apoptotic impact of PFOS in rat liver using comet assay, micronucleus test and apoptotic gene expression methods for caspase 3, caspase 8 and the protective role of curcumin on the PFOS- induced damage under chronic exposure. In this study, rats were treated either with three different PFOS doses only (0.6, 1.25 and 2.5 mg/kg) or one dose of curcumin (80 mg/kg) or three different doses of PFOS combined with 80 mg/kg dose of curcumin by gavage for 30 days at 48 h intervals. We evaluated the DNA damage via comet assay and micronucleus test. Doses of PFOS increased micronucleus frequency (p < 0.05) and strongly induced DNA damage in liver in two different parameters; i: the damaged cell percentage and ii: genetic damage index. Curcumin prevented the formation of DNA damage induced by PFOS and curcumin substance applied with PFOS caused a decrease in the micronucleus frequency. PFOS increased apoptotic gene expression but curcumin decreased the expression levels of caspase 3 and 8.
Dietary fish oil protects against Gentamicin, Cisplatin, Uranyl Nitrate, and Nitric oxide donor/metabolite-induced nephrotoxicity and oxidative damage in rat kidney
2016, Fish and Fish Oil in Health and Disease Prevention
Long-term exposure to certain pharmaceutical and environmental agents such as gentamicin, cisplatin, uranyl nitrate, sodium nitroprusside, sodium nitrite, and arginine, produce nephrotoxicity and cause severe damage to the kidneys. Dietary consumption of fish and/or fish oil (FO) containing long-chain n–3 (LCn3) polyunsaturated fatty acids is known to have extensive health benefits. They have been shown to retard the progression of various forms of cancers, depression, diabetes, arthritis, asthma, cardiovascular, neurological, and renal disorders and have also been found to improve kidney functions. Here, we discuss the protective effects of FO on drug- and chemical-induced nephrotoxicity and oxidative damage. The administration of the above mentioned agents caused severe renal damage as evident by an increase in serum creatinine, cholesterol, and blood urea nitrogen along with a decrease in certain enzymes of carbohydrate metabolism, brush border membrane (BBM), and oxidative stress. BBM phosphate (Pi) transport in the rat kidney was also reduced. However, dietary FO consumption markedly reversed the effects of these drugs and chemicals by increasing energy metabolism, BBM integrity, and Pi transport. These drugs are known to generate reactive oxygen species that cause damage to mitochondria, microsomes, peroxisomes, lysosomes, and BBM of renal proximal tubules, thus altering their functions. Dietary LCn3 fatty acids in FO affect membrane organization, fluidity, permeability, and other properties by altering membrane fatty acid composition. FO-induced changes, at least in part, can also be attributed to improved antioxidant defense mechanisms that accelerate repair and regeneration of damaged cellular membranes. In conclusion, we propose that dietary FO consumption may provide a cushion for prolonged clinical use of these drugs by ameliorating drug-induced nephrotoxicity and prevents multiple adverse effects inflicted upon by the exposure of these environmental contaminants.
Hepatotoxicity of Herbal Preparations
2012, Zakim and Boyer's Hepatology

View all citing articles on Scopus

View full text

Liver apoptosis

Abstract

Pathology

Cell

Trends Cell Biol

Cell

Hepatology

J Hepatol

Int Rev Exp Pathol

Trends Cell Biol

Trends Cell Biol

Hepatology

Febs Lett

Cell

Biochim Biophys Acta

Trends Cell Biol

Exp Cell Res

Febs Lett

Immunol Today

Febs Lett

TIBS

Cell

Biochem Biophys Res Commun

Lancet

Cancer Lett

Hum Pathol

J Hepatol

Trends Pharmacol Sci

Exp Mol Pathol

J Comp Pathol

Intern Hepatol Commun

Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics

Br J Cancer

Electron microscopic observations on Councilman-like acidophilic bodies and other forms of acidophilic changes in human liver cells

Am J Pathol

The ultrastucture of acidophilic “Councilman-like” bodies in the liver

Am J Pathol

Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats

Carcinogenesis

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

J Cell Biol

A new method to detect apoptosis in paraffin section: in situ end-labeling of fragmented DNA

J Histochem Cytochem

Induction of apoptosis in the murine liver with recombinant human activin A

Hepatology

Apoptotic bodies in a murine model of alcoholic liver disease: reversibility of ethanol-induced changes

J Pathol

The streaming liver. II. Hepatocyte life history

Liver

The streaming liver: a slow, divided flow

Hepatology

The significance of cell death by apoptosis in hepatobiliary disease

J Gastroenterol Hepatol

Occurrence of cell death (apoptosis) during the involution of liver hyperplasia

Lab Invest

Detection of apoptosis and expression of apoptosis-related proteins during human intrahepatic bile duct development

Am J Pathol

Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

Nature

Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis

J Pathol

Calcium-dependent cell death. Role of the endonuclease, protein kinase C, and chromatin conformation

An NY Acad Sci

Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen

FASEB J

Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation

EMBO J

A biochemical hallmark of apoptosis: internucleosomal degradation of the genome

Cancer Metast Rev

Ca²⁺ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen