This new book entitled "Non-Alcoholic Fatty Liver Disease Research 2016" covers a selection of recent research topics and current review articles in the field of nonalcoholic fatty liver disease ...(NAFLD) that have been recently published in a monographic Special Issue of the International Journal of Molecular Sciences (IJMS) journal. <false,>NAFLD is an “umbrella” definition that encompasses a spectrum of histopathological liver changes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with/without fibrosis, “cryptogenic” cirrhosis and hepatocellular carcinoma. <false,>NAFLD has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. <false,>It is now becoming increasingly clear that the clinical and economic burden of NAFLD does not only affect the liver, but also affects the risk of developing cardiovascular disease, type 2 diabetes mellitus, colo-rectal neoplasms, chronic kidney disease and other extra-hepatic diseases that have a considerable impact on health-care expenditures. <false,>Against this background, further research is needed to better understand the natural history, and the molecular pathogenesis of NAFLD, as well as to elucidate the underlying mechanisms by which NAFLD contributes to the increased cardiometabolic risk, and to disclose novel and effective treatment strategies for this increasingly prevalent and burdensome disease.<false,>Some of the leading international researchers in this area expressed a willingness to contribute to this book providing an updated, state-of-the-art view on the aforementioned topics, and also suggesting novel research avenues for NAFLD.
In recent years, the incidence rate of nonalcoholic fatty liver disease (NAFLD) has ascended with the increasing number of metabolic diseases such as obesity and diabetes, which will bring great ...medical burden to society. At present, multiple scientific experiments have found that the CCR4-NOT complex can participate in regulating obesity and energy metabolism. This study is designed to explore the role and mechanism of CCR4-NOT transcription complex subunit 7 (CNOT7), a subunit of the CCR4-NOT complex in liver lipid deposition.
To establish the NAFLD cell model, palmitic acid (PA) was utilized to stimulate HepG2 cells and LO2 cells, promoting intracellular lipid deposition. CNOT7 was knockdown by siRNA and lentivirus to evaluate the effect of CNOT7 in NAFLD.
Our results demonstrated that the expression of CNOT7 was increased in the NAFLD cell model. After knocking down CNOT7, the lipid deposition declined in HepG2 or LO2 cells treated by PA reduced. We found the lipid synthesis genes and the lipid uptake and transport factors in the CNOT7 knockdown group were significantly downregulated compared to the non-knockdown group. Furthermore, knockdown of CNOT7 might promote fatty acid oxidation.
Knocking down CNOT7 can improve lipid deposition and CNOT7 may be a potential therapeutic target for NAFLD.
•CNOT7 could become a target for improving liver lipid deposition.•After knocking down CNOT7, the lipid synthesis genes were significantly downregulated.•The knock down of CNOT7 also affected lipid uptake and transport factors and fatty acid oxidation genes.•CNOT7 could regular plenty of metabolic genes.
Tartaric acid (TA) has been shown beneficial effects on blood pressure and lipid levels. However, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. This study aimed to ...investigate the role of TA in experimental NAFLD. Mice were fed a Western diet for 8 weeks, followed by administration of TA or a vehicle for an additional 12 weeks while continuing on the Western diet. Blood biochemistry including transaminases and glucose tolerance test and liver tissue RNA sequencing (RNA-seq), lipid content, and histology were investigated. The HepG2 cell line was used to explore the mechanism by which TA regulates lipid metabolism. We found that TA significantly improved weight gain, insulin resistance, hepatic steatosis, inflammation and fibrosis in Western diet-fed mice. By comparing gene expression differences, we found that TA affects pathways related to lipid metabolism, inflammatory response, and fibrosis. Furthermore, TA effectively reduced oleic acid-induced lipid accumulation in HepG2 cells and downregulated the genes associated with fatty acid synthesis, which were enriched in the AMP-activated protein kinase (AMPK) signaling pathway. TA also enhanced the phosphorylation of AMPK which could be reverted by the AMPK inhibitor Compound C in HepG2 cells. Our study suggests that TA improves experimental NAFLD by activating the AMPK signaling pathway. These findings indicate that TA may serve as a potential therapy for the human NAFLD.
The identification of biomarkers for the early diagnosis of nonalcoholic fatty liver disease (NAFLD) is urgently needed. Here, we aimed to identify NAFLD biomarkers in the early stages of steatosis ...(SS) and nonalcoholic steatohepatitis (NASH) based on differential gene expression from bioinformatics data.
A meta-analysis was performed from transcriptomic databases retrieved from public repositories containing data from biopsies of patients at various stages of NAFLD development. The status of the selected molecules was validated in the serum of patients with NAFLD by ELISA.
We identified 121 differentially expressed genes (DEGs) associated with SS and 402 associated with NASH. Gene Ontology (GO) enrichment revealed that the altered genes were primarily associated with dysfunction of primary cellular processes, and pathway analyses were mainly related to cholesterol metabolism. We identified ACSS2, PCSK9, and CYP7A1 as candidate biomarkers for SS and ANGPTL3, CD36, CYP51A1, FASN, FAS, FDFT1, and LSS as candidate biomarkers for NASH.
By experimental validation of bioinformatics data from patients with NAFLD, we identified promising biomarkers for detecting SS and NASH that might be useful for screening and diagnosing early NAFLD stages in humans.
Background & Aims Some patients with nonalcoholic fatty liver disease (NAFLD) develop liver-related complications and have higher mortality than other patients with NAFLD. We determined the accuracy ...of simple, noninvasive scoring systems in identification of patients at increased risk for liver-related complications or death. Methods We performed a retrospective, international, multicenter cohort study of 320 patients diagnosed with NAFLD, based on liver biopsy analysis through 2002 and followed through 2011. Patients were assigned to mild-, intermediate-, or high-risk groups based on cutoff values for 2 of the following: NAFLD fibrosis score, aspartate aminotransferase/platelet ratio index, FIB-4 score, and BARD score. Outcomes included liver-related complications and death or liver transplantation. We used multivariate Cox proportional hazard regression analysis to adjust for relevant variables and calculate adjusted hazard ratios (aHRs). Results During a median follow-up period of 104.8 months (range, 3−317 months), 14% of patients developed liver-related events and 13% died or underwent liver transplantation. The aHRs for liver-related events in the intermediate-risk and high-risk groups, compared with the low-risk group, were 7.7 (95% confidence interval CI: 1.4−42.7) and 34.2 (95% CI: 6.5−180.1), respectively, based on NAFLD fibrosis score; 8.8 (95% CI: 1.1−67.3) and 20.9 (95% CI: 2.6−165.3) based on the aspartate aminotransferase/platelet ratio index; and 6.2 (95% CI: 1.4−27.2) and 6.6 (95% CI: 1.4−31.1) based on the BARD score. The aHRs for death or liver transplantation in the intermediate-risk and high-risk groups compared with the low-risk group were 4.2 (95% CI: 1.3−13.8) and 9.8 (95% CI: 2.7−35.3), respectively, based on the NAFLD fibrosis scores. Based on aspartate aminotransferase/platelet ratio index and FIB-4 score, only the high-risk group had a greater risk of death or liver transplantation (aHR = 3.1; 95% CI: 1.1−8.4 and aHR = 6.6; 95% CI: 2.3−20.4, respectively). Conclusions Simple noninvasive scoring systems help identify patients with NAFLD who are at increased risk for liver-related complications or death. NAFLD fibrosis score appears to be the best indicator of patients at risk, based on HRs. The results of this study require external validation.
Is MASLD lost in translation in mice? Gunes, Aysim; Estall, Jennifer L.
Trends in endocrinology and metabolism,
06/2024, Volume:
35, Issue:
6
Journal Article
Peer reviewed
Lack of preclinical model translation is often blamed for failed drug development. Here we discuss mouse models within the context of human steatotic liver disease (SLD). Variables such as aging and ...non-food hepatic stressors are often ignored but could explain challenges in reproducing the human disease in a laboratory.
Lack of preclinical model translation is often blamed for failed drug development. Here we discuss mouse models within the context of human steatotic liver disease (SLD). Variables such as aging and non-food hepatic stressors are often ignored but could explain challenges in reproducing the human disease in a laboratory.
The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease ...(NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest®, ELF™ or Pro-C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver-related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on “omics” approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes.
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