Current Experimental Perspectives on the Clinical Progression of Alcoholic Liver Disease (original) (raw)
Related papers
Gastroenterology, 2006
Background & Aims-The biguanide drug metformin has recently been found to improve steatosis and liver damage in animal models and in humans with non-alcoholic steatohepatitis. Methods-The aim of the present study was to determine whether metformin also prevents steatosis and liver damage in mouse models of acute and chronic alcohol exposure. Results-Acute ethanol exposure caused a >20-fold increase in hepatic lipids, peaking 12 hours after administration. Metformin treatment significantly blunted the ethanol effect by >60%. Although metformin is a known inducer of AMP kinase (AMPK) activity, the hepatoprotective property of metformin did not correlate with activation of AMPK or of AMPK-dependent pathways. Instead, the protective effects of metformin correlated with complete prevention of the upregulation of plasminogen activator inhibitor (PAI)-1 caused by ethanol. Indeed, a similar protective effect against acute alcohol-induced lipid accumulation was observed in PAI-1 −/− mice. Hepatic fat accumulation caused by chronic enteral ethanol feeding was also prevented by metformin or by knocking out PAI-1. Under these conditions, necroinflammatory changes caused by ethanol were also significantly attenuated. Conclusions-Taken together, these findings suggest a novel mechanism of action for metformin and identify a new role of PAI-1 in hepatic injury caused by ethanol. Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world. 1 Fat accumulation in the liver is 1 of the first characteristics of the onset of ALD. 2 Originally thought to be a pathologically inert histologic change, more recent work indicates that steatosis may play a critical role not only in the initiation, but also in the progression of ALD. 3 Indeed, results of clinical studies indicate that patients with fatty liver are more vulnerable to developing later stages of the disease (eg, fibrosis and cirrhosis 4). Because of an incomplete understanding of the mechanism(s) involved in the disease process, a universally accepted therapy to prevent or reverse ALD in humans is lacking. Therefore, better understanding of the biochemical and pathologic changes that cause alcohol-induced fatty liver may lead to therapies that not only prevent steatosis, but may also have therapeutic effects on later stages of ALD.
Pathogenesis of alcohol-induced liver disease: Classical concepts and recent advances
Journal of Gastroenterology and Hepatology, 2011
Alcoholic liver disease (ALD) is a primary consequence of heavy and prolonged drinking. ALD contributes to the bulk of liver disease burden worldwide. Progression of ALD is a multifactorial and multistep process that includes many genetic and environmental risk factors. The molecular pathogenesis of ALD involves alcohol metabolism and secondary mechanisms such as oxidative stress, endotoxin, cytokines and immune regulators. The histopathological manifestation of ALD occurs as an outcome of complex but controlled interactions between hepatic cell types. Hepatic stellate cells (HSCs) are the key drivers of fibrogenesis, but transformation of hepatocytes to myofibroblastoids also implicate parenchymal cells as playing an active role in hepatic fibrogenesis. Recent discoveries indicate that lipogenesis during the early stages of ALD is a risk for advancement to cirrhosis. Other recently identified novel molecules and physiological/cell signaling pathways include fibrinolysis, osteopontin, transforming growth factor-b-SMAD and hedgehog signaling, and involvement of novel cytokines in hepatic fibrogenesis. The observation that ALD and non-alcoholic steatohepatitis share common pathways and genetic polymorphisms suggests operation of parallel pathogenic mechanisms. Future research involving genomics, epigenomics, deep sequencing and non-coding regulatory elements holds promise to identify novel diagnostic and therapeutic targets for ALD. There is also a need for adequate animal models to study pathogenic mechanisms at the molecular level and targeted therapy. ALD pathogenesis: Recent concepts D Seth et al. D Seth et al. ALD pathogenesis: Recent concepts ALD pathogenesis: Recent concepts D Seth et al. ALD pathogenesis: Recent concepts D Seth et al. ALD pathogenesis: Recent concepts D Seth et al.
Alcoholic liver disease: Current insights into cellular mechanisms
World Journal of Biological Chemistry, 2021
The primary aim of the World Journal of Biological Chemistry (WJBC, World J Biol Chem) is to provide scholars and readers from various fields of biological chemistry a platform to publish high-quality basic and clinical research articles and communicate their research findings online. WJBC mainly publishes articles reporting research results and findings obtained in the field of biological chemistry and covering a wide range of topics including bioenergetics, cell biology, chromosomes
Alcoholic liver disease: Pathogenesis, management, and novel targets for therapy
Journal of Gastroenterology and Hepatology, 2013
Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease (ALD). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD, which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL-22/STAT3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide (LPS), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD. We further discuss the findings of recent translational studies and potential therapeutic targets.
Advances in alcoholic liver disease
Current Gastroenterology Reports, 2004
Cytokines are mediators of cellular communication produced by multiple liver cell types. Cytokines can directly induce either necrosis or apoptosis. They can also recruit such cells as neutrophils and lymphocytes, which can mediate liver damage. Increased levels of hepatotoxic cytokines such as tumor necrosis factor-’are documented in alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH) and have been shown to play a mechanistic role in both of these disease processes. Transforming growth factor-βs a profibrotic cytokine that is critical in hepatic fibrosis. Beneficial cytokines, such as interleukin (IL)-10 and-6, also exist. Such beneficial cytokines as adiponectin are made outside the liver and appear to protect against ALD and NASH. This article reviews the relevance of cytokines in human and experimental forms of liver injury, focusing on modulation of cytokines and the use of beneficial cytokines in treatment and prevention of liver injury in ALD, NASH, and hepatitis C.
Pathogenesis of Alcoholic Liver Disease???Recent Advances
Alcoholism: Clinical and Experimental Research, 2002
The article summarizes the proceedings of a symposium on recent advances in research on the pathogenesis of alcoholic liver disease at the 2001 RSA meeting in Montreal, Canada. The chairs were Amin A. Nanji and Samuel W. French. The presentations were (1) Role of inflammatory mediators in alcoholic liver injury by Amin A. Nanji, (2) Role of endotoxin, lipopolysaccharide binding protein, CD14 and Toll receptors in alcoholic liver injury by Grace Su, (3) Fatty acid ethyl esters: toxicity, metabolism and markers of ethanol intake by Michael Laposata, and (4) Cyclic changes in gene expression when rats are fed alcohol at a constant rate by Samuel W. French.
Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets
Gastroenterology, 2011
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism-associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. We review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD, improving our understanding of its pathogenesis. Despite this progress, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets.
Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives
International Journal of Molecular Sciences
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging ...
Toxicologic Pathology, 2004
Steatosis is a frequent pathologic stage in alcoholic liver disease (ALD). Although the mechanisms for increased susceptibility of steatotic liver to injury have been postulated, the ability of these hepatocytes to proliferate and withstand injury is unknown. There are conflicting reports on the status of hepatocyte regeneration following chronic alcohol ingestion. Hence, the objective of this study was to investigate the temporal dynamics between the pattern of liver injury and hepatocyte proliferation during the steatosis stage of ALD. Alcoholic steatosis was induced in male Sprague-Dawley rats by feeding an ethanol (EtOH)-containing Lieber-DeCarli liquid diet for a period of 5 weeks. Microvesicular steatosis was evident in H&E sections by three weeks in the EtOH-treated rats, which further developed into panlobular macrovesicular steatosis by 5 weeks. Plasma transaminase activities indicated progressive increase in liver injury peaking at 3 weeks with significant but mild decrease at 4 and 5 weeks. CYP2E1 protein and activity was significantly increased in EtOH-fed rats as measured by Western blot and pNP hydroxylation assay. PCNA analysis of liver sections indicated that EtOH-treated rats had a significantly higher number of cells in S phase of cell division at weeks 1 (3.20 ± 0.19), 2 (7.03 ± 0.92), and 3 (4.23 ± 1.41) when compared to controls (1.5 ± 0.22). NF-κB DNA binding and Cyclin D1 proteins increased significantly in the EtOH-treated rats corresponding with enhanced hepatic proliferation. These data suggest the transient decline in liver injury during alcoholic steatosis is due to enhanced NF-κB-dependent hepatocyte proliferation.
New role of plasminogen activator inhibitor-1 in alcohol-induced liver injury
Journal of Gastroenterology and Hepatology, 2008
Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of plasminogen activators, thereby playing a major role in fibrinolysis. Whereas hyperfibrinolysis is common in alcoholic cirrhosis, hypofibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of ALD has been unclear. The role of PAI-1 was therefore investigated in models of early (steatosis), intermediate (inflammation/necrosis) and late (fibrosis) stages of alcoholic liver disease. For example, hepatic steatosis caused by both acute and chronic ethanol was blunted by inhibiting PAI-1 activation. This effect of inhibiting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the absence of PAI-1. The results from that study also indicated that PAI-1 plays a critical role in both acute and chronic hepatic inflammation. Lastly, knocking out PAI-1 potently protected against experimental hepatic fibrosis; the mechanism of this protective effect appears to be mediated predominantly by extracellular matrix (ECM) resolution by matrix metalloproteases, which are indirectly inhibited by PAI-1. In summary, targeting PAI-1 protects against all three stages of ALD in model systems. The mechanisms by which PAI-1 contributes to these disease stages appear to not only involve the 'classical' function of PAI-1 (i.e. in mediating fibrinolysis), but also other functions of this protein. These data support a role of PAI-1 in the initiation and progression of ALD, and suggest that PAI-1 may be a useful target for clinical therapy to halt or blunt disease progression.