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Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis
Nonalcoholic steatohepatitis is a major cause of cirrhosis and liver cancer. It is associated with visceral adiposity and the metabolic syndrome and is nearly as common as type 2 diabetes. Metabolic stress, inflammation, and fibrosis are the primary pathogenic mechanisms.
Journal Article
Nothing : John Cage and 4' 33\
\"The story of the composer John Cage's famous composition of four minutes and 33 seconds of empty sheet music, and its first performance by the pianist David Tudor\"-- Provided by publisher.
Book
Risk of Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease
Growing evidence suggests that nonalcoholic fatty liver disease is associated with an increased risk of cardiovascular disease beyond that conferred by established risk factors.
Nonalcoholic fatty liver disease encompasses a spectrum of pathologic conditions, ranging from simple steatosis to nonalcoholic steatohepatitis and cirrhosis. The disease has reached epidemic proportions and is the most common cause of chronic liver disease in Western countries.
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Approximately 20 to 30% of adults in the general population in Western countries have nonalcoholic fatty liver disease, and its prevalence increases to 70 to 90% among persons who are obese or have diabetes; such patients are also at increased risk for the development of advanced fibrosis and cirrhosis.
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Recognition of the importance of nonalcoholic fatty liver disease and its . . .
Journal Article
Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis
NAFLD is becoming much more common, and will soon be the major underlying aetiology for liver transplantation. This article discusses the evidence that NAFLD is a multisystem disease and outlines the factors that determine interindividual variation in the development and progression of NAFLD.
NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).
Key Points
NAFLD is a spectrum of progressive liver disease that includes steatosis, NASH, fibrosis, cirrhosis and hepatocellular carcinoma
NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus
NAFLD, and especially NASH, are associated with an increased risk of morbidity and mortality related to the liver and cardiovascular system
NAFLD is also associated with an increased risk of developing type 2 diabetes mellitus
Considerable interindividual variation exists in the severity of NAFLD and the risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors
Journal Article
Glycointeractions in bacterial pathogenesis
Many important interactions between bacterial pathogens and their hosts are highly specific binding events that involve host or pathogen carbohydrate structures (glycans). Glycan interactions can mediate adhesion, invasion and immune evasion and can act as receptors for toxins. Several bacterial pathogens can also enzymatically alter host glycans to reveal binding targets, degrade the host cell glycans or alter the function of host glycoproteins. In recent years, high-throughput screening technologies, such as lectin, glycan and mucin microarrays, have transformed the field by identifying new bacterial–host glycointeractions, which are crucial for colonization, persistence and disease. In this Review, we discuss interactions involving both host and bacterial glycans that have a role in bacterial pathogenesis. We also highlight recent technological advances that have illuminated the glycoscience of microbial pathogenesis.
Journal Article
MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition
Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.
MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, interacts directly with NLRP3 at the Walker B motif that hydrolyzes ATP, as defined by a protease-susceptibility assay, mutational analysis, and surface plasmon resonance analysis.
Journal Article
The genetics of NAFLD
NAFLD is a complex disease. Considerable variability exists in the severity and risk of morbidity and mortality among individuals with NAFLD, which could be influenced by genetic and environmental factors. Here, the authors discuss the latest knowledge on the genetics of NAFLD and how this genetic variation might determine disease phenotype and progression.
NAFLD is a disease spectrum ranging from simple steatosis, through steatohepatitis to fibrosis and, ultimately, cirrhosis. This condition is characterized by considerable interpatient variability in terms of severity and rate of progression: although a substantial proportion of the population is at risk of progressive disease, only a minority experience associated morbidity. As such, NAFLD is best considered a complex disease trait resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers. Much ongoing research is focused on identifying the genetic factors that contribute to NAFLD pathogenesis. This Review describes the current status of the field, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including
PNPLA3
, influence disease progression.
Key Points
NAFLD is a spectrum of progressive liver disease encompassing steatosis, NASH, fibrosis and cirrhosis
NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus
Considerable interindividual variation exists in terms of NAFLD severity and risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors
Candidate-gene studies and hypothesis-generating genome-wide association studies have provided key insights into the pathogenesis of NAFLD, with multiple genetic modifiers being described
PNPLA3
remains the most well-validated gene associated with all aspects of the NAFLD spectrum
Although considerable progress has been made in elucidating how the
PNPLA3
rs738409 (encoding Ile148Met) variant promotes NAFLD, it remains unclear why this gene also associates so strongly with inflammatory and fibrosis
Journal Article
Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease
ObjectiveLiver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD.DesignPatients with biopsy-proven NAFLD and age-matched controls were recruited from the liver and gastroenterology clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell-free circulating DNA methylation of PPARγ was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing.Results26 patients with biopsy-proven NAFLD were included. Quantitative plasma DNA methylation of PPARγ stratified patients into mild (Kleiner 1–2) and severe (Kleiner 3–4) fibrosis (CpG1: 63% vs 86%, p<0.05; CpG2: 51% vs 65% p>0.05). Hypermethylation at the PPARγ promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis.ConclusionsDifferential DNA methylation at the PPARγ promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPARγ could potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.
Journal Article