TET2 regulation of alcoholic fatty liver via Srebp1 mRNA in paraspeckles
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Abstract:
Epigenetic modifications have emerged as key regulators of metabolism-related complex diseases including the alcoholic fatty liver disease (AFLD) prevalent chronic liver disorder with significant economic implications. Building upon previous research that emphasizes ten-eleven translocation (TET) proteins' involvement in adipocyte insulin sensitization and fatty acid oxidation, we explored the role of TET2 protein in AFLD pathogenesis which catalyzes 5-methylcytosine into 5-hydroxymethylcytosine in DNA/RNA. Our findings revealed that TET2 deficiency exacerbates AFLD progression. And TET2 influenced the expression and activity of sterol regulatory element binding protein 1 (SREBP1), a key regulator of hepatic lipid synthesis, by modulatingKeywords:
Steatohepatitis
Non-alcoholic fatty liver disease (NAFLD) is a complex disease characterized by a massive accumulation of lipids in the liver, with a continuous progression of simple steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma.Non-alcoholic fatty liver disease is associated with obesity, insulin resistance, and metabolic syndrome; it is a severe public health risk and is currently the most common liver disease of the world.In addition to the fatty infiltration of the liver in non-alcoholic fatty liver disease patients, the field of liver transplantation faces similar obstacles.NAFLD and NASH primarily involve lipotoxicity, inflammation, oxidative stress, and insulin resistance.However, the precise mechanisms and treatments remain unclear.Therapeutic approaches encompass exercise, weight control, as well as treatments targeting antioxidants and anti-inflammatory pathways.The role of animal models in research has become crucial as a key tool to explore the molecular mechanisms and potential treatments for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.Here, we summarized the current understanding of the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis and discussed animal models commonly used in recent years.
Steatohepatitis
Lipotoxicity
Steatosis
Liver disease
Alcoholic fatty liver
Alcoholic Hepatitis
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Non-alcoholic fatty liver disease (NAFLD) is currently conceptualised as a clinical spectrum that results from a ‘multiple-hit’ process which begins with simple steatosis and subsequently renders the hepatocytes susceptible to a variety of insults. Ultimately, more serious liver injuries like non-alcoholic steatohepatitis (NASH) and cirrhosis may develop. Although the metabolic syndrome is considered the crucial player in the pathogenesis of NAFLD, recent studies have highlighted novel pathophysiological mechanisms in this clinical entity.To discuss the pathophysiology of NAFLD based on the hypothesis that simple steatosis and NASH are discrete entities rather than two points on a spectrum.A literature search was conducted in August 2012 on PubMed, Ovid Embase, Ovid Medline and Scopus using the following search terms: steatosis, non-alcoholic steatohepatitis, pathophysiology, fatty liver, natural history and genetics.Simple steatosis and NASH appear as two distinct pathophysiological entities and progression from pure fatty liver to NASH appears to be so rare as to warrant publication. The possible pathogenetic pathways specifically related to NASH are highlighted.Although simple steatosis and non-alcoholic steatohepatitis are currently viewed as two histological subtypes of the unique spectrum of non-alcoholic fatty liver disease, the two conditions are likely distinct not only from a histological but also from a pathophysiological standpoint. Efforts to distinguish simple steatosis from non-alcoholic steatohepatitis using non-invasive modalities should be informed by the current pathophysiology of these two clinical entities.
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Steatohepatitis
Liver function
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Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are usually associated with obesity and metabolic syndrome, are considerable health and economic issues due to the rapid increase of their prevalence in Western society. Histologically, the diseases are characterised by steatosis, hepatic inflammation, and if further progressed, fibrosis. Dietary-induced mouse models are widely used in investigations of the development and progression of NAFLD and NASH; these models attempt to mimic the histological and metabolic features of the human diseases. However, the majority of dietary mouse models fail to reflect the whole pathophysiological spectrum of NAFLD and NASH. Some models exhibit histological features similar to those seen in humans while lacking the metabolic context, while others resemble the metabolic conditions leading to NAFLD in humans but fail to mimic the whole histological spectrum, including progression from steatosis to liver fibrosis, and thus fail to mimic NASH. This review summarises the advantages and disadvantages of the different dietary-induced mouse models of NAFLD and NASH, with a focus on the genetic background of several commonly used wild-type mouse strains as well as gender and age, which influence the development and progression of these liver diseases.
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The prevalence of Type 2 diabetes is expected to increase in parallel with obesity rates and the ageing population. Recent studies show that Type 2 diabetes is associated with a twofold increase in the risk of non-alcoholic fatty liver disease, a leading cause of chronic liver disease. Individuals with non-alcoholic steatohepatitis, a more advanced stage of non-alcoholic fatty liver disease, are specifically at risk of developing fibrosis/cirrhosis (end-stage liver disease) and hepatocellular carcinoma; therefore, identifying individuals (with Type 2 diabetes) who are likely to develop hepatic complications is paramount. In the present clinical review, we discuss the potential impact of non-alcoholic fatty liver disease diagnosis on Type 2 diabetes, and the putative risk factors for developing non-alcoholic steatohepatitis and non-alcoholic steatohepatitis fibrosis. We highlight the limitations of currently used tools in non-alcoholic fatty liver disease diagnosis and staging, and provide an insight into future developments in the field. We present an example of a non-alcoholic fatty liver disease screening protocol and discuss the therapeutic options currently available to our patients.
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Non-alcoholic fatty liver disease is the most prevalent liver disease with a global prevalence of 25%. The frequency of non-alcoholic fatty liver disease and the percentage of people with severe liver disease are expected to rise given the ongoing obesity pandemic, the rise in diabetes, and other factors. This will have a significant effect on health care expenditure and the need for liver transplantation, for which non-alcoholic steatohepatitis is already on track to overtake alcoholic steatohepatitis as the most prevalent reason. Non-alcoholic fatty liver disease is characterized by the triglyceride accumulation in the cytoplasm of hepatocytes. Patients with non-alcoholic fatty liver disease who have advanced fibrosis and non-alcoholic steatohepatitis are at much higher risk of negative outcomes, such as overall mortality and liver-specific morbidity and death. It is a multisystemic clinical illness entity that manifests extrahepatic conditions like polycystic ovarian syndrome, type 2 diabetes, chronic renal disease, hypothyroidism, and psoriasis. In fact, cardiovascular disease, cancer, and liver-related problems are the three leading causes of death in non-alcoholic fatty liver disease patients, in that order. Non-alcoholic fatty liver disease is further divided into two subtypes hepatic steatosis and non-alcoholic steatohepatitis ranging from milder to more aggressive form of the disease.
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Steatosis
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Dyslipidemia
Alcoholic fatty liver
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The aim of the study was to compare the features of immune response in patients with alcoholic liver disease and non-alcoholic steatohepatitis.There was investigated immune status of 46 patients with alcoholic liver disease and 34 patients with non-alcoholic steatohepatitis.It was found the resemblance of the immune regulation of pathogenesis in both diseases. It was also established that in the history of alcoholic liver disease necrosis starts earlier because of loosing immune regulation of programmed cell death. This leads to forming liver cirrhosis in younger age.
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Purpose of review Non-alcoholic fatty liver disease is an increasingly prevalent form of chronic liver disease that progresses to cirrhosis and hepatocellular carcinoma in a fraction of the overweight and sedentary population. Knowledge is advancing rapidly in describing the magnitude of the problem, how non-alcoholic fatty liver disease should be diagnosed, and what treatment options are available. This review examines data from the past year on key clinical aspects of non-alcoholic fatty liver disease. Recent findings New data on the epidemiology of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and insulin resistance is constantly emerging, and new treatment options are being evaluated. Using serum alanine aminotransferase elevations to identify patients with possible chronic liver diseases is unreliable and should possibly be abandoned. Similarly, ultrasound is unreliable in detecting non-alcoholic fatty liver disease in severely obese patients. Imaging by computed tomography or magnetic resonance may be used in high-risk groups, such as those with features of the metabolic syndrome, but cost-effective means of identifying patients with non-alcoholic steatohepatitis are not available. Treatment options include weight loss, exercise and drugs. Bariatric surgery may be beneficial with respect to liver disease. Summary The presence of non-alcoholic steatohepatitis should be sought in individuals with features of insulin resistance and other features of the metabolic syndrome, because these patients are most at risk of developing advanced liver disease. Current data indicate that lifestyle modifications that include weight loss and exercise should be the primary treatment option.
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Non-alcoholic fatty liver disease represents a spectrum of liver diseases which occurs in the absence of alcohol consumption in amounts considered injurious to the liver. Non-alcoholic fatty liver disease includes both non-alcoholic fatty liver and non-alcoholic steatohepatitis. We present an integrated approach that utilizes both clinical and laboratory studies to diagnose and manage a patient with suspected non-alcoholic steatohepatitis. The goals of treatment include (1) correction of the underlying risk factors, (2) avoidance of factors that promote progression of liver disease, and (3) specific treatment of non-alcoholic steatohepatitis.
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