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Cells Mar 2020The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is... (Review)
Review
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver's physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
Topics: Animals; Humans; Liver; Liver Diseases; Mitochondria; Mitophagy; Receptors, Cell Surface; Signal Transduction
PubMed: 32244304
DOI: 10.3390/cells9040837 -
World Journal of Gastroenterology Oct 2014The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world's third largest risk factor for disease and disability;... (Review)
Review
The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world's third largest risk factor for disease and disability; it is a causal factor of 60 types of diseases and injuries and a concurrent cause of at least 200 others. Liver is the main organ responsible for metabolizing ethanol, thus it has been considered for long time the major victim of the harmful use of alcohol. Ethanol and its bioactive products, acetaldehyde-acetate, fatty acid ethanol esters, ethanol-protein adducts, have been regarded as hepatotoxins that directly and indirectly exert their toxic effect on the liver. A similar mechanism has been postulated for the alcohol-related pancreatic damage. Alcohol and its metabolites directly injure acinar cells and elicit stellate cells to produce and deposit extracellular matrix thus triggering the "necrosis-fibrosis" sequence that finally leads to atrophy and fibrosis, morphological hallmarks of alcoholic chronic pancreatitis. Even if less attention has been paid to the upper and lower gastrointestinal tract, ethanol produces harmful effects by inducing: (1) direct damaging of the mucosa of the esophagus and stomach; (2) modification of the sphincterial pressure and impairment of motility; and (3) alteration of gastric acid output. In the intestine, ethanol can damage the intestinal mucosa directly or indirectly by altering the resident microflora and impairing the mucosal immune system. Notably, disruption of the intestinal mucosal barrier of the small and large intestine contribute to liver damage. This review summarizes the most clinically relevant alcohol-related diseases of the digestive tract focusing on the pathogenic mechanisms by which ethanol damages liver, pancreas and gastrointestinal tract.
Topics: Alcohol Drinking; Alcoholism; Animals; Disease Progression; Ethanol; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Liver; Liver Diseases, Alcoholic; Pancreas; Pancreatic Diseases; Prognosis; Risk Assessment; Risk Factors
PubMed: 25356028
DOI: 10.3748/wjg.v20.i40.14652 -
Journal of Translational Medicine May 2023Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the... (Review)
Review
Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. Many metabolic enzymes, including alcohol dehydrogenases such as ADH, CYP2E1, and CATacetaldehyde dehydrogenases ALDHsand nonoxidative metabolizing enzymes such as SULT, UGT, and FAEES, are involved in the metabolism of ethanol, the main component in alcoholic beverages. Ethanol consumption changes the functional or expression profiles of various regulatory factors, such as kinases, transcription factors, and microRNAs. Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. For example, ethanol damages the intestinal barrier, resulting in the release of endotoxins and alterations in intestinal flora content and bile acid metabolism. However, ALD therapies show low effectiveness. Therefore, this review summarizes ethanol metabolism pathways and highly influential pathogenic mechanisms and regulatory factors involved in ALD pathology with the aim of new therapeutic insights.
Topics: Humans; Liver Diseases, Alcoholic; Liver; Ethanol; Alcoholism; Alcohol Dehydrogenase
PubMed: 37143126
DOI: 10.1186/s12967-023-04166-8 -
Frontiers in Cellular and Infection... 2023The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis... (Review)
Review
The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis - liver cancer are significant and common part of liver diseases. The pathogenesis of liver diseases is generally as followed: inflammation and other pathogenic factors cause persistent damage to the liver, leading to the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix. Patients with chronic hepatitis have a high risk of developing into liver fibrosis, cirrhosis, and even life-threatening liver cancer, which poses a great threat to public health.As the first organ to come into contact with blood from the gut, the liver is profoundly affected by the intestinal flora and its metabolites, with leaky gut and flora imbalance being the triggers of the liver's pathological response. So far, no one has reviewed the role of intestinal flora in this process from the perspective of the progression of hepatitis-cirrhosis-liver cancer and this article reviews the evidence supporting the effect of intestinal flora in the progression of liver disease.
Topics: Humans; Gastrointestinal Microbiome; Liver Cirrhosis; Liver; Hepatitis; Fibrosis; Liver Neoplasms
PubMed: 36968098
DOI: 10.3389/fcimb.2023.1140126 -
Gastroenterology Aug 2019Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK)...
BACKGROUND & AIMS
Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis.
METHODS
Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1), SAB (Sab), or JNK1 and JNK2 (Jnk1+2) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah/Rag2/Il2rg/NOD (FRGN) mice to create mice with humanized livers.
RESULTS
Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1 mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1 mice given APAP alone. Sab mice or Jnk1+2 mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver.
CONCLUSIONS
In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.
Topics: Acetaminophen; Adult; Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Overdose; Endoplasmic Reticulum Stress; Hepatocytes; Humans; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphoproteins; Steroids; Transplantation Chimera; Up-Regulation; Valproic Acid
PubMed: 31029706
DOI: 10.1053/j.gastro.2019.04.023 -
International Journal of Molecular... Aug 2022The liver is responsible for extremely important functions in the human body. In the liver's structure, we distinguish between connective tissue (stroma) and parenchyma,... (Review)
Review
The liver is responsible for extremely important functions in the human body. In the liver's structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver-hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
Topics: Carcinoma, Hepatocellular; Chemokines; Chemokines, CXC; Humans; Liver; Liver Neoplasms
PubMed: 36012108
DOI: 10.3390/ijms23168846 -
BioMed Research International 2018The liver is the main metabolic organ in the body especially in lipometabolism and glycometabolism. Carbohydrates and fats disorders can result in insulin resistance in... (Review)
Review
The liver is the main metabolic organ in the body especially in lipometabolism and glycometabolism. Carbohydrates and fats disorders can result in insulin resistance in the liver. Metabolic imbalance can even lead to life-threatening conditions. Therefore, it is essential to maintain the normal metabolic function of the liver. When the liver is in a pathological state, liver metabolism homeostasis is damaged, and metabolic disorders will further aggravate liver disease. Consequently, it is essential to determine the relationship between liver diseases and metabolic disorders. Here we review a lot of evidence that liver diseases are closely related to lipometabolism and glycometabolism. Although the disorder of the liver metabolism is caused by different liver diseases, the break of metabolic balance is determined by changes in the state of the liver. We discuss the relationship between liver disease and metabolic changes, outline the process of how metabolic changes are regulated by liver diseases, and describe the role which metabolic changes play in the process and prognosis of liver disease.
Topics: Animals; Carbohydrate Metabolism; Humans; Lipid Metabolism; Liver; Liver Diseases
PubMed: 31205932
DOI: 10.1155/2018/1287127 -
International Journal of Molecular... Sep 2021The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver... (Review)
Review
The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option for patients suffering from end-stage liver disease is liver transplantation. However, the number of donor livers required by far surpasses the supply, leading to a significant organ shortage. Cellular therapies play an increasing role in the restoration of organ function and can be integrated into organ transplantation protocols. Different types and sources of stem cells are considered for this purpose, but highly specific immune cells are also the focus of attention when developing individualized therapies. In-depth knowledge of the underlying mechanisms governing cell differentiation and engraftment is crucial for clinical implementation. Additionally, novel technologies such as ex vivo machine perfusion and recent developments in tissue engineering may hold promising potential for the implementation of cell-based therapies to restore proper organ function.
Topics: Animals; Cell- and Tissue-Based Therapy; End Stage Liver Disease; Humans; Immunotherapy; Liver; Liver Diseases; Liver Regeneration; Liver Transplantation; Regenerative Medicine; Stem Cell Transplantation
PubMed: 34638617
DOI: 10.3390/ijms221910276 -
Stem Cell Research & Therapy May 2023Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient... (Review)
Review
Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.
Topics: Animals; Humans; End Stage Liver Disease; Liver; Hepatocytes; Liver Diseases; Cell- and Tissue-Based Therapy; Liver Regeneration; Cell Differentiation
PubMed: 37231461
DOI: 10.1186/s13287-023-03370-z -
EBioMedicine Nov 2022Reliable biomarkers for organ quality assessment during normothermic machine perfusion (NMP) are desired. ATP (adenosine triphosphate) production by oxidative... (Clinical Trial)
Clinical Trial
BACKGROUND
Reliable biomarkers for organ quality assessment during normothermic machine perfusion (NMP) are desired. ATP (adenosine triphosphate) production by oxidative phosphorylation plays a crucial role in the bioenergetic homeostasis of the liver. Thus, detailed analysis of the aerobic mitochondrial performance may serve as predictive tool towards the outcome after liver transplantation.
METHODS
In a prospective clinical trial, 50 livers were subjected to NMP (OrganOx Metra) for up to 24.ßh. Biopsy and perfusate samples were collected at the end of cold storage, at 1.ßh, 6.ßh, end of NMP, and 1.ßh after reperfusion. Mitochondrial function and integrity were characterized by high-resolution respirometry (HRR), AMP, ADP, ATP and glutamate dehydrogenase analysis and correlated with the clinical outcome (L-GrAFT score). Real-time confocal microscopy was performed to assess tissue viability. Structural damage was investigated by histology, immunohistochemistry and transmission electron microscopy.
FINDINGS
A considerable variability in tissue viability and mitochondrial respiration between individual livers at the end of cold storage was observed. During NMP, mitochondrial respiration with succinate and tissue viability remained stable. In the multivariate analysis of the 35 transplanted livers (15 were discarded), area under the curve (AUC) of LEAK respiration, cytochrome c control efficiency (mitochondrial outer membrane damage), and efficacy of the mitochondrial ATP production during the first 6.ßh of NMP correlated with L-GrAFT.
INTERPRETATIONS
Bioenergetic competence during NMP plays a pivotal role in addition to tissue injury markers. The AUC for markers of outer mitochondrial membrane damage, ATP synthesis efficiency and dissipative respiration (LEAK) predict the clinical outcome upon liver transplantation.
FUNDING
This study was funded by a Grant from the In Memoriam Dr. Gabriel Salzner Stiftung awarded to SS and the Tiroler Wissenschaftsfond granted to TH.
Topics: Humans; Adenosine Triphosphate; Cold Ischemia; Liver; Mitochondria; Organ Preservation; Perfusion; Prospective Studies; Respiration
PubMed: 36374770
DOI: 10.1016/j.ebiom.2022.104311