Degradation of splicing factor SRSF3 contributes to progressive liver disease

Serine-rich splicing factor 3 (SRSF3) plays a critical role in liver function and its loss promotes chronic liver damage and regeneration. As a consequence, genetic deletion of SRSF3 in hepatocytes caused progressive liver disease and ultimately led to hepatocellular carcinoma. Here we show that SRSF3 is decreased in human liver samples with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or cirrhosis that was associated with alterations in RNA splicing of known SRSF3 target genes. Hepatic SRSF3 expression was similarly decreased and RNA splicing dysregulated in mouse models of NAFLD and NASH. We showed that palmitic acid–induced oxidative stress caused conjugation of the ubiquitin-like NEDD8 protein to SRSF3 and proteasome-mediated degradation. SRSF3 was selectively neddylated at lysine 11 and mutation of this residue (SRSF3-K11R) was sufficient to prevent both SRSF3 degradation and alterations in RNA splicing. Lastly, prevention of SRSF3 degradation in vivo partially protected mice from hepatic steatosis, fibrosis, and inflammation. These results highlight a neddylation-dependent mechanism regulating gene expression in the liver that is disrupted in early metabolic liver disease and may contribute to the progression to NASH, cirrhosis, and ultimately hepatocellular carcinoma.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

Related Links:

Authors: Carrier P, Debette-Gratien M, Jacques J, Loustaud-Ratti V Abstract The global population is aging, and so the number of older cirrhotic patients is increasing. Older patients are characterised by a risk of frailty and comorbidities, and age is a risk factor for mortality in cirrhotic patients. The incidence of non-alcoholic fatty liver disease as an aetiology of cirrhosis is increasing, while that of chronic viral hepatitis is decreasing. Also, cirrhosis is frequently idiopathic. The management of portal hypertension in older cirrhotic patients is similar to that in younger patients, despite the greater ri...
Source: World Journal of Hepatology - Category: Gastroenterology Tags: World J Hepatol Source Type: research
CONCLUSIONS: Our study showed that the upregulation of NLRP3 inflammasome activated by cardiolipin is crucial in NASH pathogenesis, which might provide a novel potential role of cardiolipin blockade in the treatment of NASH. PMID: 31599445 [PubMed - in process]
Source: European Review for Medical and Pharmacological Sciences - Category: Drugs & Pharmacology Tags: Eur Rev Med Pharmacol Sci Source Type: research
Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the two major types of primary liver tumour. Both are increasing in incidence in the UK, in the case of HCC because of the increasing prevalence of chronic liver disease, particularly caused by alcohol and non-alcoholic fatty liver disease. They have a poor overall prognosis because of late presentation and the presence of underlying liver cirrhosis in patients with HCC. Patients usually present with a liver mass or jaundice. Assessment is primarily radiological by means of computed tomography and/or magnetic resonance imaging.
Source: Medicine - Category: Internal Medicine Authors: Tags: Tumours Source Type: research
In this study, new perspective markers for inflammation, oxidative stress, apoptosis, and fibrogenesis; emerging scoring models for detecting hepatic steatosis and fibrosis; and new genetic, epigenetic, and multiomic studies are discussed. As isolated biochemical parameters are not specific or sensitive enough to predict the presence of NASH and fibrosis, there is a tendency to use various markers and combine them into mathematical algorithms. Several predictive models and scoring systems have been developed. Current data suggests that panels of markers (NAFLD fibrosis score, Fib-4 score, BARD score, and others) are useful...
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Review Source Type: research
Publication date: Available online 21 September 2019Source: Journal of Clinical and Experimental HepatologyAuthor(s): Shivaram Prasad Singh, Rakesh Kumar BarikAbstractNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD encompasses a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. However, despite the growing recognition of this important disease burden, there are significant challenges to accurately and non-invasively diagnose the various forms of NAFLD, especially to differentiate benig...
Source: Journal of Clinical and Experimental Hepatology - Category: Gastroenterology Source Type: research
Publication date: Available online 20 September 2019Source: Journal of Clinical and Experimental HepatologyAuthor(s): Arka De, Ajay DusejaAbstractThe histological spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), NASH related cirrhosis and hepatocellular carcinoma (HCC). Ballooning degeneration of hepatocytes with or without fibrosis is the key-feature which differentiates NASH from NAFL. Liver biopsy is the only reliable method for diagnosing NAFL and differentiating it from NASH. Although the epidemiology of NAFL...
Source: Journal of Clinical and Experimental Hepatology - Category: Gastroenterology Source Type: research
Authors: Polyzos SA, Kountouras J, Goulas A, Duntas L Abstract Conflicting data link nonalcoholic fatty liver disease (NAFLD), a disease with no currently approved treatment, with selenium (Se) and selenoprotein P (SELENOP), a glycoprotein synthesized and primarily secreted by the hepatocytes, functioning as a Se transporter from the liver to other tissues. This review aims to summarize the evidence between Se, SELENOP, and NAFLD, which may hopefully clarify whether current data on Se and SELENOP in NAFLD warrant further investigation for their diagnostic and therapeutic potential. Most, albeit not all, experimenta...
Source: Hormones - Category: Endocrinology Tags: Hormones (Athens) Source Type: research
Abstract The intimate connection and the strict mutual cooperation between the gut and the liver realizes a functional entity called gut-liver axis. The integrity of intestinal barrier is crucial for the maintenance of liver homeostasis. In this mutual relationship, the liver acts as a second firewall towards potentially harmful substances translocated from the gut, and is, in turn, is implicated in the regulation of the barrier. Increasing evidence has highlighted the relevance of increased intestinal permeability and consequent bacterial translocation in the development of liver damage. In particular, in patient...
Source: World Journal of Gastroenterology - Category: Gastroenterology Authors: Tags: World J Gastroenterol Source Type: research
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the leading liver diseases worldwide. NAFLD is characterised by hepatic steatosis and may progress to an inflammatory condition termed non-alcoholic steatohepatitis, (NASH), liver cirrhosis and hepatocellular carcinoma. It became evident in the last years that NAFLD pathophysiology is complex and involves diverse immunological and metabolic pathways. An association between intestinal signals (e.g. derived from the gut microbiota) and the development of obesity and its metabolic consequences such as NAFLD are increasingly recognized. Preclinical studies have sh...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
Publication date: Available online 3 September 2019Source: Redox BiologyAuthor(s): Mi Hye Kim, Jung Bae Seong, Jae-Won Huh, Yong Chul Bae, Hyun-Shik Lee, Dong-Seok LeeAbstractNon-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally. NAFLD—which can develop into liver fibrosis, nonalcoholic steatohepatosis, cirrhosis, and hepatocellular carcinoma—is defined as an excess accumulation of fat caused by abnormal lipid metabolism and excessive reactive oxygen species (ROS) generation in hepatocytes. Recently, we reported that Peroxiredoxin 5 (Prx5) plays an essential role i...
Source: Redox Biology - Category: Biology Source Type: research
More News: Biomedical Science | Cancer & Oncology | Carcinoma | Cirrhosis | Fatty Liver Disease (FLD) | Genetics | Hepatocellular Carcinoma | Liver | Liver Cancer | Liver Disease | Non-alcoholic Fatty Liver Diseases (NAFLD) | Urology & Nephrology