scholarly journals Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alessandra Scagliola ◽  
Annarita Miluzio ◽  
Gabriele Ventura ◽  
Stefania Oliveto ◽  
Chiara Cordiglieri ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Disease Progression ◽  
Lipid Accumulation ◽  
Initiation Factor ◽  
Acid Oxidation ◽  
Protective Effects ◽  
Alcoholic Fatty Liver ◽  
Factor C

AbstractA postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPβ, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.

Resveratrol Ameliorates Alcoholic Fatty Liver by Inducing Autophagy

2016 ◽  
Vol 44 (06) ◽  
pp. 1207-1220 ◽  
Author(s):  
Liying Tang ◽  
Fengli Yang ◽  
Zhirui Fang ◽  
Chengmu Hu
Keyword(s):  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Early Stage ◽  
Low Density Lipoprotein ◽  
Specific Inhibitor ◽  
Density Lipoprotein ◽  
Protective Effects ◽  
Alcoholic Fatty Liver

Alcoholic fatty liver (AFL) is early stage of alcoholic liver disease, which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. The pathogenesis of AFL is associated with excessive lipid accumulation in hepatocytes. Resveratrol (RES), a dietary polyphenol found in red wines and grapes, has been shown to have a hepatoprotective effect. Autophagy is a crucial physiological process in cellular catabolism that involves the regulation of lipid droplets. Autophagy maintains a balance between protein synthesis, degradation and self-recycling. In the present study, we evaluated the protective effects of RES (10[Formula: see text]mg/kg, 30[Formula: see text]mg/kg, 100[Formula: see text]mg/kg) on AFL mice fed with an ethanol Lieber-DeCarli liquid diet, and HepG2 cells in the presence of oleic acid and alcohol to investigate whether resveratrol could induce autophagy to attenuate lipid accumulation. The results showed that RES (30[Formula: see text]mg/kg and 100[Formula: see text]mg/kg) treatment significantly attenuated hepatic steatosis and lowered the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low density lipoprotein cholesterol (LDL-C). H&E staining showed that RES reduced hepatic lipid accumulation. Transmission electron microscopy (TEM) images showed that RES treatment increased the number of autophagosomes and promoted the formation of autophagy. Western blot analysis showed that RES treatment increased the levels of microtubule-associated protein light chain3- II (LC3-II) and Beclin1, decreased expression of p62 protein. In addition, in vitro studies also demonstrated that RES led to the formation of acidic vesicular organelles (AVOs), however, 3-Methyladenine (3-MA), a specific inhibitor of autophagy, obviously inhibited the above effects of RES. In conclusion, RES has protective effects on alcoholic hepatic steatosis, and the potential mechanism might be involved in inducing autophagy.

scholarly journals Serum miR-375 Levels Are Closely Related to Disease Progression from HBV Infection to HBV-Related Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Weilu Zhang ◽  
Ting Fu ◽  
Zhenjun Guo ◽  
Ye Zhang ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B ◽  
Disease Progression ◽  
Cellular Proliferation ◽  
Hbv Infection ◽  
Cell Counting ◽  
Specificity And Sensitivity ◽  
And Migration ◽  
Proliferation And Migration

Background. There is an urgent need to identify ideal serological biomarkers that not only are closely related to disease progression from hepatitis B virus (HBV) infection to hepatocellular carcinoma (HCC) but also have high specificity and sensitivity. We conducted this study to analyze whether miR-375 has a potential value in the early prediction of the progression from HBV-related hepatitis or cirrhosis to HCC. Methods. A total of 177 participants were enrolled. Receiver operating characteristic (ROC) curve was used to evaluate the predictive capability of selected miR-375 for HBV-HCC. We upregulated the miR-375 expression in HepG2, HepG2.2.15, and HepAD38 cells to determine its effect on cellular proliferation and migration, in vitro using Cell Counting Kit-8 (CCK-8) assays. Results. Serum miR-375 levels decreased in order from healthy controls to chronic hepatitis B (CHB) without cirrhosis, followed by cirrhosis, and finally, HBV-HCC patients. miR-375 levels were significantly lower in HBeAg-positive and HBV DNA-positive patients than negative (P<0.05) and significantly lower in patients with elevated alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) than normal levels (P<0.05). miR-375 might be a biomarker for HBV-HCC, with a high area under the curve (AUC) of 0.838 (95% confidence interval (CI) 0.780 to 0.897; sensitivity: 73.9%; specificity: 93.0%). The AUC (0.768 vs. 0.584) and sensitivity (93.8% vs. 75.0%) for miR-375 were higher than those for AFP. The overexpression of miR-375 noticeably inhibited proliferation and migration in HepG2, HepG2.2.15, and HepAD38, especially in HepG2.2.15 and HepAD38, which are stably infected with HBV. Conclusions. Serum miR-375 levels are closely related to disease progression from HBV-related hepatitis or cirrhosis to HCC.

scholarly journals Nootkatone, a Dietary Fragrant Bioactive Compound, Attenuates Dyslipidemia and Intramyocardial Lipid Accumulation and Favorably Alters Lipid Metabolism in a Rat Model of Myocardial Injury: An In Vivo and In Vitro Study

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5656
Author(s):  
M.F. Nagoor Meeran ◽  
Sheikh Azimullah ◽  
M Marzouq Al Ahbabi ◽  
Niraj Kumar Jha ◽  
Vinoth-Kumar Lakshmanan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Rat Model ◽  
Lipid Accumulation ◽  
Heart Diseases ◽  
Radical Scavenging ◽  
Enzymatic Antioxidants ◽  
Protective Effects ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

In the present study, we assessed whether nootkatone (NKT), a sesquiterpene in edible plants, can provide protection against dyslipidemia, intramyocardial lipid accumulation, and altered lipid metabolism in a rat model of myocardial infarction (MI) induced by subcutaneous injections of isoproterenol (ISO, 85 mg/kg) on days 9 and 10. The rats were pre- and co-treated with NKT (10 mg/kg, p.o.) administered daily for 11 days. A significant reduction in the activities of myocardial creatine kinase and lactate dehydrogenase, as well as non-enzymatic antioxidants, and alterations in lipids and lipoproteins, along with a rise in plasma lipid peroxidation and intramyocardial lipid accumulation, were observed in ISO-treated rats. ISO administration induced alterations in the activities of enzymes/expressions that played a significant role in altering lipid metabolism. However, NKT treatment favorably modulated all biochemical and molecular parameters altered by ISO and showed protective effects against oxidative stress, dyslipidemia, and altered lipid metabolism, attributed to its free-radical-scavenging and antihyperlipidemic activities in rats with ISO-induced MI. Additionally, NKT decreased the accumulation of lipids in the myocardium as evidenced from Oil red O staining. Furthermore, the in vitro observations demonstrate the potent antioxidant property of NKT. The present study findings are suggestive of the protective effects of NKT on dyslipidemia and the underlying mechanisms. Based on our findings, it can be suggested that NKT or plants rich in NKT can be promising for use as a phytopharmaceutical or nutraceutical in protecting the heart and correcting lipid abnormalities and dyslipidemia, which are risk factors for ischemic heart diseases.

scholarly journals Implications of the Use of Eukaryotic Translation Initiation Factor 5A (eIF5A) for Prognosis and Treatment of Hepatocellular Carcinoma

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Felix H. Shek ◽  
Sarwat Fatima ◽  
Nikki P. Lee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Initiation Of Translation ◽  
Eukaryotic Translation Initiation ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a primary liver malignancy and accounts for most of the total liver cancer cases. Lack of treatment options and late diagnosis contribute to high mortality rate of HCC. In eukaryotes, translation of messenger RNA (mRNA) to protein is a key process in protein biosynthesis in which initiation of translation involves interaction of different eukaryotic translation initiation factors (eIFs), ribosome subunits and mRNAs. Eukaryotic translation initiation factor 5A (eIF5A) is one of the eIFs involved in translation initiation and eIF5A2, one of its isoforms, is upregulated in various cancers including HCC as a result of chromosomal instability, where it resides. In HCC, eIF5A2 expression is associated with adverse prognosis such as presence of tumor metastasis and venous infiltration. Based on eIF5A2 functional studies, suppressing eIF5A2 expression by short interfering RNA alleviates the tumorigenic properties of HCC cellsin vitrowhile ectopic expression of eIF5A2 enhances the aggressiveness of HCC cellsin vivoandin vitroby inducing epithelial-mesenchymal transition. In conclusion, eIF5A2 is a potential prognostic marker as well as a therapeutic target for HCC.

scholarly journals NAP1L1 Functions as a Tumor Promoter via Recruiting Hepatoma-Derived Growth Factor/c-Jun Signal in Hepatocellular Carcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Ye-wei Zhang ◽  
Qian Chen ◽  
Bo Li ◽  
Hai-Yang Li ◽  
Xue-Ke Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Growth Factor ◽  
Poor Prognosis ◽  
Quantitative Polymerase Chain Reaction ◽  
The Cancer Genome Atlas ◽  
Tumor Promoter ◽  
Mechanism Analysis ◽  
Factor C

NAP1L1 has been reported to be significantly involved in the carcinogenesis of hepatocellular carcinoma (HCC). Yet, its detailed molecular basis is still to be determined. Based on the analysis of The Cancer Genome Atlas (TCGA) database, NAP1L1 mRNA was found to be upregulated and predicted the poor prognosis initially. Subsequently, consistent with the prediction, the upregulated expression of NAP1L1 mRNA and protein levels was confirmed by quantitative polymerase chain reaction (qPCR), Western blot, and immunohistochemistry assays. Upregulated NAP1L1 protein positively promoted the disease progression and poor prognosis of HCC. In addition, NAP1L1 protein expression was considered as an independent prognostic factor in HCC. Inhibition of NAP1L1 expression by siRNA or shRNA pathway significantly reduced the cell proliferation and cell cycle transformation in vitro and in vivo. Mechanism analysis first showed that the function of NAP1L1 was to recruit hepatoma-derived growth factor (HDGF), an oncogene candidate widely documented in tumors. Furthermore, the latter interacted with c-Jun, a key oncogenic transcription factor that can induce the expression of cell cycle factors and thus stimulate the cell growth in HCC. Finally, transfecting HDGF or c-Jun could reverse the suppressive effects on HCC growth in NAP1L1-suppressed HCC cells. Our data indicate that NAP1L1 is a potential oncogene and acts via recruiting HDGF/c-Jun in HCC.

scholarly journals In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5583
Author(s):  
Guilherme Ribeiro Romualdo ◽  
Kaat Leroy ◽  
Cícero Júlio Silva Costa ◽  
Gabriel Bacil Prata ◽  
Bart Vanderborght ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
In Vitro Models ◽  
Virus Infections ◽  
Alcoholic Fatty Liver ◽  
Contaminated Food ◽  
Patient Prognosis ◽  
Key Events ◽  
Translational Modeling

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

scholarly journals A Mitochondrial Approach to Cardiovascular Risk and Disease

2019 ◽  
Vol 25 (29) ◽  
pp. 3175-3194 ◽  
Author(s):  
Caroline D. Veloso ◽  
Getachew D. Belew ◽  
Luciana L. Ferreira ◽  
Luís F. Grilo ◽  
John G. Jones ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Energy Demand ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Alcoholic Fatty Liver ◽  
Cardiovascular Morbidity And Mortality

Background: Cardiovascular diseases (CVDs) are a leading risk factor for mortality worldwide and the number of CVDs victims is predicted to rise through 2030. While several external parameters (genetic, behavioral, environmental and physiological) contribute to cardiovascular morbidity and mortality; intrinsic metabolic and functional determinants such as insulin resistance, hyperglycemia, inflammation, high blood pressure and dyslipidemia are considered to be dominant factors. Methods: Pubmed searches were performed using different keywords related with mitochondria and cardiovascular disease and risk. In vitro, animal and human results were extracted from the hits obtained. Results: High cardiac energy demand is sustained by mitochondrial ATP production, and abnormal mitochondrial function has been associated with several lifestyle- and aging-related pathologies in the developed world such as diabetes, non-alcoholic fatty liver disease (NAFLD) and kidney diseases, that in turn can lead to cardiac injury. In order to delay cardiac mitochondrial dysfunction in the context of cardiovascular risk, regular physical activity has been shown to improve mitochondrial parameters and myocardial tolerance to ischemia-reperfusion (IR). Furthermore, pharmacological interventions can prevent the risk of CVDs. Therapeutic agents that can target mitochondria, decreasing ROS production and improve its function have been intensively researched. One example is the mitochondria-targeted antioxidant MitoQ10, which already showed beneficial effects in hypertensive rat models. Carvedilol or antidiabetic drugs also showed protective effects by preventing cardiac mitochondrial oxidative damage. Conclusion: This review highlights the role of mitochondrial dysfunction in CVDs, also show-casing several approaches that act by improving mitochondrial function in the heart, contributing to decrease some of the risk factors associated with CVDs.

scholarly journals The effects of fructose and metabolic inhibition on hepatocellular carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Brittany Dewdney ◽  
Mohammed Alanazy ◽  
Rhys Gillman ◽  
Sarah Walker ◽  
Miriam Wankell ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Metabolism ◽  
Pentose Phosphate ◽  
Metabolic Effects ◽  
Alcoholic Fatty Liver ◽  
Highly Active ◽  
Pentose Phosphate Pathways ◽  
Glycine Synthesis

Abstract Hepatocellular carcinoma is rapidly becoming one of the leading causes of cancer-related deaths, largely due to the increasing incidence of non-alcoholic fatty liver disease. This in part may be attributed to Westernised diets high in fructose sugar. While many studies have shown the effects of fructose on inducing metabolic-related liver diseases, little research has investigated the effects of fructose sugar on liver cancer metabolism. The present study aimed to examine the metabolic effects of fructose on hepatocellular carcinoma growth in vitro and in vivo. Fructose sugar was found to reduce cell growth in vitro, and caused alterations in the expression of enzymes involved in the serine-glycine synthesis and pentose phosphate pathways. These biosynthesis pathways are highly active in cancer cells and they utilise glycolytic by-products to produce energy and nucleotides for growth. Hence, the study further investigated the efficacy of two novel drugs that inhibit these pathways, namely NCT-503 and Physcion. The study is the first to show that the combination treatment of NCT-503 and Physcion substantially inhibited hepatocellular carcinoma growth in vitro and in vivo. The combination of fructose diet and metabolism-inhibiting drugs may provide a unique metabolic environment that warrants further investigation in targeting hepatocellular carcinoma.

scholarly journals S100A11/ANXA2 belongs to a tumour suppressor/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development

Gut ◽  
2020 ◽  
Vol 69 (10) ◽  
pp. 1841-1854 ◽  
Author(s):  
Cyril Sobolewski ◽  
Daniel Abegg ◽  
Flavien Berthou ◽  
Dobrochna Dolicka ◽  
Nicolas Calo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Ex Vivo ◽  
Tumour Suppressor ◽  
High Grade ◽  
Genomic Alterations ◽  
Deficient Diet ◽  
Alcoholic Fatty Liver

ObjectiveHepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations.DesignThe proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses.ResultsA whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration.ConclusionCellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis.

scholarly journals eNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH

2019 ◽  
Vol 317 (4) ◽  
pp. E605-E616 ◽  
Author(s):  
Ryan D. Sheldon ◽  
Grace M. Meers ◽  
E. Matthew Morris ◽  
Melissa A. Linden ◽  
Rory P. Cunningham ◽  
...  
Keyword(s):  
Quality Control ◽  
Transcription Factor ◽  
Mitochondrial Biogenesis ◽  
Western Diet ◽  
Acid Oxidation ◽  
Related Factor ◽  
Functional Impairments ◽  
Primary Hepatocytes ◽  
Mitochondrial Quality Control

Dysregulated mitochondrial quality control leads to mitochondrial functional impairments that are central to the development and progression of hepatic steatosis to nonalcoholic steatohepatitis (NASH). Here, we identify hepatocellular localized endothelial nitric oxide synthase (eNOS) as a novel master regulator of mitochondrial quality control. Mice lacking eNOS were more susceptible to Western diet-induced hepatic inflammation and fibrosis in conjunction with decreased markers of mitochondrial biogenesis and turnover. The hepatocyte-specific influence was verified via magnetic activated cell sorting purified primary hepatocytes and in vitro siRNA-induced knockdown of eNOS. Hepatic mitochondria from eNOS knockout mice revealed decreased markers of mitochondrial biogenesis (PPARγ coactivator-1α, mitochondrial transcription factor A) and autophagy/mitophagy [BCL-2-interacting protein-3 (BNIP3), 1A/1B light chain 3B (LC3)], suggesting decreased mitochondrial turnover rate. eNOS knockout in primary hepatocytes exhibited reduced fatty acid oxidation capacity and were unable to mount a normal BNIP3 response to a mitophagic challenge compared with wild-type mice. Finally, we demonstrate that eNOS is required in primary hepatocytes to induce activation of the stress-responsive transcription factor nuclear factor erythroid 2-related factor 2 ( NRF2). Thus, our data demonstrate that eNOS is an important regulator of hepatic mitochondrial content and function and NASH susceptibility.

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