scholarly journals Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Liane Rabinowich ◽  
Oren Shibolet
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Early Recognition ◽  
Developed Countries ◽  
Common Disease ◽  
Drug Induced ◽  
Altered Expression ◽  
The Metabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrialβ-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

2020 ◽  
Vol 48 (8) ◽  
pp. 994-1007
Author(s):  
Timothy P. LaBranche ◽  
Anna K. Kopec ◽  
Srinivasa R. Mantena ◽  
Brett D. Hollingshead ◽  
Andrew W. Harrington ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Pharmaceutical Industry ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Sd Rats ◽  
Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322526
Author(s):  
Xiaolin Wang ◽  
Yong He ◽  
Bryan Mackowiak ◽  
Bin Gao
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Liver Diseases ◽  
Target Genes ◽  
Therapeutic Targets ◽  
Drug Induced ◽  
Alcoholic Fatty Liver ◽  
Altered Expression ◽  
Mrna Targets

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.

scholarly journals From NAFLD to cardiovascular disease. Is it (still) the metabolic syndrome?

2014 ◽  
Vol 87 (2) ◽  
pp. 80-86 ◽  
Author(s):  
Mihai Alexandru Munteanu ◽  
Petru Adrian Mircea
Keyword(s):  
Cardiovascular Disease ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Liver Disease ◽  
Geographical Area ◽  
Developed Countries ◽  
Active Monitoring ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Visceral Adipose

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in developed countries. The incidence of NAFLD in the general population is 30-38% deppending on the geographical area and the diagnostic method used. NAFLD is considered to be the liver manifestation of the metabolic syndrome. A better understanding of the natural evolution would have practical consequences related mainly to the need of early and aggressive diagnosis, active monitoring and therapeutic solutions. Cardiovascular disease appears to be the main cause of death in these patients. The mechanisms linking NAFLD with cardiovascular disease are not fully understood yet, but attention was focused primarily on insulin resistance. The visceral adipose tissue, the epicardial adipose tissue, the systemic inflammatory response syndrome, the lipid profile, the procoagulants factors, the oxidative stress, and type 2 diabetes mellitus, they all might play a role in the link between NAFLD and cardiovascular disease. Currently, there isn’t any medication specifically recommended for the treatment of NAFLD. Although the mechanisms underlying the association between NAFLD and cardiovascular disease are not fully known, attention must be paid to this association, given that these patients are more likely to die due to heart disease rather than liver disease.

scholarly journals Mechanisms of Non-Alcoholic Fatty Liver Disease in the Metabolic Syndrome. A Narrative Review

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 270
Author(s):  
Luca Rinaldi ◽  
Pia Clara Pafundi ◽  
Raffaele Galiero ◽  
Alfredo Caturano ◽  
Maria Vittoria Morone ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Risk Factor ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Smoking Habit ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) are two different entities sharing common clinical and physio-pathological features, with insulin resistance (IR) as the most relevant. Large evidence leads to consider it as a risk factor for cardiovascular disease, regardless of age, sex, smoking habit, cholesterolemia, and other elements of MS. Therapeutic strategies remain still unclear, but lifestyle modifications (diet, physical exercise, and weight loss) determine an improvement in IR, MS, and both clinical and histologic liver picture. NAFLD and IR are bidirectionally correlated and, consequently, the development of pre-diabetes and diabetes is the most direct consequence at the extrahepatic level. In turn, type 2 diabetes is a well-known risk factor for multiorgan damage, including an involvement of cardiovascular system, kidney and peripheral nervous system. The increased MS incidence worldwide, above all due to changes in diet and lifestyle, is associated with an equally significant increase in NAFLD, with a subsequent rise in both morbidity and mortality due to both metabolic, hepatic and cardiovascular diseases. Therefore, the slowdown in the increase of the “bad company” constituted by MS and NAFLD, with all the consequent direct and indirect costs, represents one of the main challenges for the National Health Systems.

scholarly journals Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome

2010 ◽  
Vol 69 (2) ◽  
pp. 211-220 ◽  
Author(s):  
J. Bernadette Moore
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Response To Treatment ◽  
Health Concern ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease in both adults and children worldwide. As a disease spectrum, NAFLD may progress from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. An estimated 20–35% of the general population has steatosis, 10% of whom will develop the more progressive non-alcoholic steatohepatitis associated with markedly increased risk of cardiovascular- and liver-related mortality. Development of NAFLD is strongly linked to components of the metabolic syndrome including obesity, insulin resistance, dyslipidaemia and type 2 diabetes. The recognition that NAFLD is an independent risk factor for CVD is a major public health concern. There is a great need for a sensitive non-invasive test for the early detection and assessment of the stage of NAFLD that could also be used to monitor response to treatment. The cellular and molecular aetiology of NAFLD is multi-factorial; genetic polymorphisms influencing NAFLD have been identified and nutrition is a modifiable environmental factor influencing NAFLD progression. Weight loss through diet and exercise is the primary recommendation in the clinical management of NAFLD. The application of systems biology to the identification of NAFLD biomarkers and factors involved in NAFLD progression is an area of promising research.

scholarly journals Pediatric Non-Alcoholic Fatty Liver Disease/Oboljenje Ne-Alkoholne Masne Jetre U Pedijatriji

2014 ◽  
Vol 34 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Edgard Delvin ◽  
Natasha Patey ◽  
Josée Dubois ◽  
Melanie Henderson ◽  
Émile Lévy
Keyword(s):  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Major Increase ◽  
Near Future ◽  
Alcoholic Fatty Liver Disease ◽  
Early Atherosclerosis

Summary The rapidly increasing prevalence of childhood obesity and its associated co-morbidities such as hypertriglyceridemia, hyper-insulinemia, hypertension, early atherosclerosis, metabolic syndrome, and non-alcoholic fatty liver disease are major public health concerns in many countries. Therefore the trends in child and adolescent obesity should be closely monitored over time, as in the near future, we may anticipate a major increase of young adults with the stigmata of the metabolic syndrome, and of the related non-alcoholic fatty liver disease (NAFLD), that may lead to non-alcoholic steatohepatitis.

scholarly journals Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261789
Author(s):  
Xiaoying Liu ◽  
Sarah A. Taylor ◽  
Kyle D. Gromer ◽  
Danny Zhang ◽  
Susan C. Hubchak ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Cell Activation ◽  
Stellate Cell ◽  
Binding Protein ◽  
The United States ◽  
High Fat ◽  
Altered Expression ◽  
Nonalcoholic Fatty Liver ◽  
End Stage

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.

Sign in / Sign up

Export Citation Format

Share Document