Current
Volume 3, Number 6, 2003
Contents
Molecular Mechanisms of
Liver Injury
Executive Editor: Xiao-Ming
Yin
Mechanisms of Liver Injury: An Overview Pp.483-490
Hajime
Higuchi and Gregory J. Gores
Death Receptor Activation-Induced Hepatocyte
Apoptosis and Liver Injury
Pp.491-508
Xiao-Ming
Yin and Wen-Xing Ding
CYP2E1: Biochemistry, Toxicology, Regulation
and Function in Ethanol-Induced Liver Injury Pp.509-518
Irina
Kessova and Arthur I. Cederbaum
Role of Nitric Oxide in Liver Injury Pp.519-526
Tracy
Chen, Ruben Zamora, Brian Zuckerbraun and Timothy R. Billiar
Role of the Mitochondrial Permeability
Transition in Apoptotic and Necrotic Death After Ischemia/Reperfusion Injury to
Hepatocytes Pp.527-535
J.-S.
Kim, L. He, T. Qian and J.J.
Lemasters
Mechanisms of Viral Hepatitis Induced Liver
Injury Pp.537-544
Yasunari Nakamoto and Shuichi Kaneko
Cytokine-Induced Inflammatory Liver Injuries Pp.545-559
H. Tsutsui, K. Adachi, E. Seki and K. Nakanishi
Peroxisome Proliferator-Activated Receptors,
Fatty Acid Oxidation, Steatohepatitis and Hepatocarcinogenesis Pp.561-572
Songtao Yu, Sambasiva Rao and Janardan K. Reddy
Mechanisms of Human Hepatocarcinogenesis Pp.573-588
William
B. Coleman
Abstracts
[Back to top] Mechanisms of Liver Injury: An Overview
Hajime
Higuchi and Gregory J. Gores
Liver cirrhosis, an
end-result of a wide variety of the liver diseases, is a world wide health
problem. Because of its unique organ system, i.e., portal blood supply, bile
formation and enterohepatic circulation, drug metabolism system, and sinusoidal
lining cells such as Kupffer, endothelial and stellate cells, the liver is a
target of a variety of hepatotoxic insults. Current data suggest that
hepatocyte apoptosis is an essential feature contributing to liver injury in a
wide range of acute and chronic liver diseases. With an improved understanding
of the pathophysiological role of apoptosis in liver diseases, we are now
entering an era where regulation of liver cell apoptosis is becoming a
therapeutic possibility. Inhibition of hepatocyte apoptosis using a variety of
different strategies may be therapeutically beneficial in liver injuries, such
as alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), viral hepatitis,
and cholestatic liver diseases. Considering the link between hepatocyte
apoptosis and liver fibrosis, inhibition of hepatocyte apoptosis may also be an
anti-fibrotic therapeutic strategy. Moreover, selective induction of apoptosis
of activated stellate cells would be a unique approach to induce the resolution
the phase of liver fibrosis. These concepts merit further clinical and basic
investigation.
[Back to top] Death Receptor Activation-Induced Hepatocyte
Apoptosis and Liver Injury
Xiao-Ming
Yin and Wen-Xing Ding
The TNFá receptor
super-family consists of several members sharing a sequence homology in a
unique function domain, the death domain, which is located in the intracellular
portion of the receptor. These so-called death receptors, including Fas, TNF-R1
and TRAIL-R1/TRAIL-R2, are expressed on hepatocytes. When stimulated by their
ligands, FasL, TNFa or TRAIL,
respectively, the death receptors can activate multiple death domain-initiated
apoptosis programs, including both extrinsic and intrinsic pathways. A cascade
of caspases is activated, which cleave proteins important for the cell
structure and function. Activation of the intrinsic pathway also leads to
mitochondrial release of several apoptotic proteins and mitochondrial
dysfunction, which kill the cell through both caspase-dependent and
caspase-independent mechanisms. Death receptor-induced hepatocyte apoptosis
contributes to the development of a number of liver diseases, including viral
hepatitis, inflammatory hepatitis, Wilson’s disease, alcoholic liver disease,
endotoxiemia-induced liver failure and ischemia/reperfusion-induced liver
damage. This article comprehensively reviews the mechanisms of induction and
regulation of death receptor-initiated apoptosis in hepatocytes, examines how
these molecular events affect our understanding of the pathogenesis of these
diseases and further discusses the potential therapeutic application of the
knowledge. We hope we can provide a cohesive and integrated perspective on the
many aspects of these complicated processes.
[Back to top] CYP2E1: Biochemistry, Toxicology, Regulation
and Function in Ethanol-Induced Liver Injury
Irina
Kessova and Arthur I. Cederbaum
Ethanol-induced
oxidative stress appears to play a major role in mechanisms by which ethanol
causes liver injury. Many pathways have been suggested to contribute to the
ability of ethanol to induce a state of oxidative stress. One central pathway
appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by
ethanol. CYP2E1 is of interest because of its ability to metabolize and
activate many toxicological substrates, including ethanol, to more reactive,
toxic products. Levels of CYP2E1 are elevated under a variety of physiological
and pathophysiological conditions, and after acute and chronic alcohol
treatment. CYP2E1 is also an effective generator of reactive oxygen species
such as the superoxide anion radical and hydrogen peroxide, and in the presence
of iron catalysts, produces powerful oxidants such as the hydroxyl radical.
This Review Article summarizes some of the biochemical and toxicological
properties of CYP2E1, and briefly describes the use of HepG2 cell lines
developed to constitutively express the human CYP2E1 in assessing the actions
of CYP2E1. Regulation of CYP2E1 is quite complex and will be briefly reviewed.
Possible therapeutic implications for treatment of alcoholic liver injury by
inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed,
followed by some future directions which may help to understand the actions of
CYP2E1 and its role in alcoholic liver injury.
[Back to top] Role of Nitric Oxide in Liver Injury
Tracy
Chen, Ruben Zamora, Brian Zuckerbraun and Timothy R. Billiar
The complex role
of nitric oxide (NO) in the liver can be explained by its patterns of
regulation and unique biochemical properties. With a broad range of direct and
indirect molecular targets, NO acts as an inhibitor or agonist of cell
signaling events. In the liver, constitutively generated NO maintains the
hepatic microcirculation and endothelial integrity, while inducible NO synthase
(iNOS)-governed NO production can be either beneficial or detrimental. For
instance, NO potentiates the hepatic oxidative injury in warm
ischemia/reperfusion, while iNOS expression protects against hepatic apoptotic
cell death seen in models of sepsis and hepatitis. Anti-apoptotic actions are
either cyclic nucleotide dependent or independent, including the expression of
heat shock proteins, prevention of mitochondrial dysfunction, and inhibition of
caspase activity by S-nitrosation. Whether NO protects or injures is probably
determined by the type of insult, the abundance of reactive oxygen species
(ROS), the source and amount of NO production and the cellular redox status of
liver. Through the use of pharmacological NO donors or NOS gene transfer in
conjunction with genetically altered knockout animals, the physiological and
pathophysiological roles of NO in liver function can be explored in more
detail. The purpose of this paper is to review the current understanding of the
role of NO in liver injury.
[Back to top] Role of the Mitochondrial Permeability
Transition in Apoptotic and Necrotic Death After Ischemia/Reperfusion Injury to
Hepatocytes
J.-S. Kim, L. He, T. Qian and J.J. Lemasters
Reperfusion of
ATP-depleted tissues after warm or cold ischemia causes pH-dependent necrotic
and apoptotic cell death. In hepatocytes and other cell types as well, the mechanism
underlying this reperfusion-induced cell death involves onset of the
mitochondrial permeability transition (MPT). Opening of permeability transition
(PT) pores in the mitochondrial inner membrane initiates the MPT, an event
blocked by cyclosporin A (CsA) and pH less than 7.4. Thus, both acidotic pH and
CsA prevent MPT-dependent reperfusion injury. Glycine also blocks
reperfusion-induced necrosis but acts downstream of PT pore opening by
stabilizing the plasma membrane. After the MPT, ATP availability from
glycolysis or other source determines whether cell injury after reperfusion
progresses to ATP depletion-dependent necrosis or ATP-requiring apoptosis.
Thus, apoptosis and necrosis after reperfusion share a common pathway, the MPT.
Cell injury progressing to either necrosis or apoptosis by shared pathways can
be more aptly termed necrapoptosis.
[Back to top] Mechanisms of Viral Hepatitis Induced Liver
Injury
Yasunari
Nakamoto and Shuichi Kaneko
Among seven human
hepatitis viruses (A to E, G and TT virus), hepatitis B (HBV) and C (HCV)
viruses are able to persist in the host for years and principally contribute to
the establishment of chronic hepatitis. During the course of persistent
infection, continuous intrahepatic inflammation maintains a cycle of liver cell
destruction and regeneration that often terminates in hepatocellular carcinoma
(HCC). While the expression and retention of viral proteins in hepatocytes may
influence the severity and progression of liver disease, the mechanisms of
liver injury in viral hepatistis are defined to be due not to the direct
cytopathic effects of viruses, but to the host immune response to viral
proteins expressed by infected hepatocytes. In the process of liver injury,
hepatocellular death (apoptosis) induced by the proapoptotic molecules of T
cells activated following antigen recognition triggers a cascade of antigen
nonspecific effector systems and causes necroinflammatory disease. Accordingly,
the regulation of the immune response, e.g., via the cell death pathways, in
chronically infected patients should prevent the development of HCC.
[Back to top] Cytokine-Induced Inflammatory Liver Injuries
H.
Tsutsui, K. Adachi, E. Seki and K. Nakanishi
IL-18 is a
pleiotropic cytokine and is produced by various types of cells including
activated macrophages, particularly Kupffer cells. IL-18 has potential to
activate inflammatory responses through induction of IFN-g production in
collaboration with IL-12. Somewhat paradoxically, IL-18 also has the capacity
to induce allergic responses via induction of IL-4 production by T helper cells
and to activate mast cells and basophils to release atopic effector molecules
such as histamine. Indeed, IL-18 is involved in inflammatory tissue injuries,
such as Crohn’s disease and atherosclerosis, and also in hyper IgE and atopic
dermatitis. IL-18 is particularly important for induction of experimental liver
diseases. Endotoxin-induced liver injury or Fas ligand-induced hepatitis is
caused by endogenous IL-18 in mice. Moreover, patients with liver diseases such
as fulminant hepatitis, liver cirrhosis due to hepatitis virus infection and
primary biliary cirrhosis show elevation of serum levels of IL-18, that
correlates with the corresponding disease severity. Therefore, endogenous IL-18
plays a major role in induction of some types of liver injuries in mice and
human. NKT cells that express both T cell receptor and NK cell marker are
abundant in the liver of mice and human. Recent studies have revealed that NKT
cells participate in some types of liver injuries, such as concanavalin
A-induced T cell-mediated hepatitis and malaria hepatitis. In this review
article, we focus on IL-18-involving liver damages and NKT-cell-mediated liver
injuries.
[Back to top] Peroxisome Proliferator-Activated Receptors,
Fatty Acid Oxidation, Steatohepatitis and Hepatocarcinogenesis
Songtao
Yu, Sambasiva Rao and Janardan K. Reddy
Fatty acids are metabolized
in the liver by b-oxidation in mitochondria and peroxisomes
and by w-oxidation in microsomes. Peroxisomal b-oxidation is responsible for the metabolism
of very long chain fatty acids and mitochondrial b-oxidation
is responsible for the oxidation of short, medium and long chain fatty acids.
Very long chain fatty acids are also metabolized by the cytochrome P450 CYP4A w-oxidation system to dicarboxylic acids. Both
peroxisomal b-oxidation and microsomal w- oxidation lead to the generation of H2O2.
The genes encoding peroxisomal, microsomal and some mitochondrial fatty acid
metabolizing enzymes in the liver are transcriptionally regulated by peroxisome
proliferator-activated receptor a (PPARa). Sustained activation of PPARa by peroxisome proliferators has been shown
to induce hepatocellular carcinomas in rats and mice. The peroxisome
proliferator-induced carcinogenic effect has been attributed to transcriptional
activation of PPARa regulated genes and
the resulting excessive generation of H2O2. Evidence from
mice lacking fatty acyl-CoA oxidase (AOX), PPARa and
PPARa/AOX has confirmed the role of PPARa in the development of hepatocellular
carcinomas. In addition, mice lacking AOX developed steatohepatitis and
provided clues regarding the molecular mechanism responsible for steatosis and
steatohepatitis and the role of unmetabolized AOX substrates in the activation
of PPARa.
[Back to top] Mechanisms of Human Hepatocarcinogenesis
William
B. Coleman
The major risk
factors and etiological agents responsible for development of hepatocellular
carcinoma in humans have been identified and characterized. Among these are
chronic infection with hepatitis B virus or hepatitis C virus, exposure to
aflatoxin B1, and cirrhosis of any etiology (including alcoholic
cirrhosis and cirrhosis associated with genetic liver diseases). Both chronic
hepatitis and cirrhosis represent major preneoplastic conditions of the liver
as the majority of hepatocellular carcinomas arise in these pathological
settings. Hepatocarcinogenesis represents a linear and progressive process in
which successively more aberrant monoclonal populations of hepatocytes evolve.
Regenerative hepatocytes in focal lesions in the inflamed liver (chronic
hepatitis or cirrhosis) give rise to hyperplastic hepatocyte nodules, and these
progress to dysplastic nodules, which are thought to be the direct precursor of
hepatocellular carcinoma. In most cases, the neoplastic transformation of
hepatocytes results from accumulation of genetic damage during the repetitive
cellular proliferation that occurs in the injured liver in response to
paracrine growth factor and cytokine stimulation. Hepatocellular carcinomas
exhibit numerous genetic abnormalities (including chromosomal deletions, rearrangements,
aneuploidy, gene amplifications, and mutations), as well as epigenetic
alterations (including modulation of DNA methylation). These genetic and
epigenetic alterations combine to activate positive mediators of cellular
proliferation (including cellular proto-oncogenes and their mitogenic signaling
pathways) and inactivate negative mediators of cellular proliferation
(including tumor suppressor genes), resulting in cells with autonomous growth
potential. However, hepatocellular carcinomas exhibit a high degree of genetic
heterogeneity, suggesting that multiple molecular pathways may be involved in
the genesis of subsets of hepatocellular neoplasms. Continued investigation of
the mechanisms of hepatocarcinogenesis will refine our current understanding of
the molecular and cellular basis for neoplastic transformation in liver,
enabling the development of effective strategies for prevention and/or more
effective treatment of hepatocellular carcinoma.