scholarly journals Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia

2021 ◽  
Author(s):  
Huabo Wang ◽  
Jie Lu ◽  
Frances Alencastro ◽  
Alexander Roberts ◽  
Julia Fiedor ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Liver Disease ◽  
Cross Talk ◽  
Fatty Liver Disease ◽  
Target Genes ◽  
Type I ◽  
Wild Type ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease ◽  
Hepatic Adenomatosis

The Myc bHLH-ZIP transcription factor is deregulated by most cancers. As a heterodimer with the bHLH-ZIP protein Max, Myc regulates target genes that contribute to metabolism and proliferation. This "Myc Network" cross-talks with the "Mlx Network" comprised of the Myc-like bHLH-ZIP proteins MondoA and ChREBP and the Max-like bHLH-ZIP protein Mlx. This "Extended Myc Network" regulates genes with both common and distinct functions. We have generated hepatocytes lacking Mlx (mlxKO) or Mlx+Myc (double KO or DKO) and quantified their abilities to replace dying hepatocytes in a murine model of Type I tyosinemia. We find that this function deteriorates as the Extended Myc Network is progressively dismantled. Genes dysregulated in mlxKO and DKO hepatocytes include those involved in translation and mitochondrial function. The Myc and Mlx Networks thus cross-talk with the latter playing a disproportionate role. mycKO and mlxKO mice also develop non-alcoholic fatty liver disease and mlxKO and DKO mice develop extensive hepatic adenomatosis not observed in wild-type, mycKO, chrebpKO or mycKOxchrebpKO mice. In addition to demonstrating cooperation between the Myc and Mlx Networks, this study reveals the latter to be more important in maintaining metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.

scholarly journals Identification and functional characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease.

2021 ◽  
Author(s):  
Jane I. Grove ◽  
Peggy Cho Kiu Lo ◽  
Nick Shrine ◽  
Julian Barwell ◽  
Louise V. Wain ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Causal Variant ◽  
Wild Type ◽  
Alcoholic Fatty Liver ◽  
Triglyceride Accumulation ◽  
Donor Skin ◽  
Alcoholic Fatty Liver Disease ◽  
Rare Causal Variant

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays. Results: We identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species. Conclusion: We have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.

scholarly journals Molecular pathways involved in the improvement of non-alcoholic fatty liver disease

2013 ◽  
Vol 51 (1) ◽  
pp. 167-179 ◽  
Author(s):  
Gilberto Paz-Filho ◽  
Claudio Alberto Mastronardi ◽  
Brian J Parker ◽  
Ainy Khan ◽  
Antonio Inserra ◽  
...  
Keyword(s):  
Body Weight ◽  
Liver Disease ◽  
Liver Injury ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Glutathione Metabolism ◽  
Wild Type ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are components of the metabolic syndrome. Serum leptin levels are elevated in obesity, but the role of leptin in the pathophysiology of the liver involvement is still unclear. To identify the effects and mechanisms by which leptin influences the pathogenesis of NAFLD, we performed epididymal white adipose tissue (eWAT) transplantation from congenic wild-type mice into the subcutaneous dorsal area ofLepob/obrecipient mice and compared the results with those of theLepob/obsham-operated mice. The mice were followed for 102–216 days. During killing, the transplanted mice had significantly lost body weight and exhibited significantly higher leptin levels, improved glucose tolerance, and lower liver injury scores than the sham-operated mice. Liver microarray analysis showed that novel pathways related to GA-binding protein (GABP) transcription factor targets, pheromone binding, and olfactory signaling were differentially expressed in the transplanted mice. Our data also replicate pathways known to be involved in NAFLD, such as those involved in the regulation of microRNAs, lipid, glucose, and glutathione metabolism, peroxisome proliferator-activated receptor signaling, cellular regulation, carboxylic acid processes, iron, heme, and tetrapyrrole binding, immunity and inflammation, insulin signaling, cytochrome P450 function, and cancer. Conclusion: wild-type eWAT transplantation intoLepob/obmice led to improvements in metabolism, body weight, and liver injury, possibly attributed to the production of leptin by the transplanted eWAT. These improvements were accompanied by the differential expression of novel pathways. The causal relationship between GABP downregulation and NAFLD improvement remains to be determined.

scholarly journals Activating Transcription Factor 6 Is Necessary and Sufficient for Alcoholic Fatty Liver Disease in Zebrafish

PLoS Genetics ◽  
2014 ◽  
Vol 10 (5) ◽  
pp. e1004335 ◽  
Author(s):  
Deanna L. Howarth ◽  
Claudia Lindtner ◽  
Ana M. Vacaru ◽  
Ravi Sachidanandam ◽  
Orkhontuya Tsedensodnom ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Activating Transcription Factor ◽  
Necessary And Sufficient ◽  
Alcoholic Fatty Liver Disease

scholarly journals A Review of FoxO1-Regulated Metabolic Diseases and Related Drug Discoveries

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 184 ◽  
Author(s):  
Shiming Peng ◽  
Wei Li ◽  
Nannan Hou ◽  
Niu Huang
Keyword(s):  
Transcription Factor ◽  
Liver Disease ◽  
Energy Metabolism ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Regulation ◽  
Metabolic Diseases ◽  
Alcoholic Fatty Liver ◽  
Related Drug ◽  
Alcoholic Fatty Liver Disease

FoxO1 is a conserved transcription factor involved in energy metabolism. It is tightly regulated by modifications on its mRNA and protein and responds to environmental nutrient signals. FoxO1 controls the transcription of downstream genes mediating metabolic regulation. Dysfunction of FoxO1 pathways results in several metabolic diseases, including diabetes, obesity, non-alcoholic fatty liver disease, and atherosclerosis. Here, we summarize the mechanism of FoxO1 regulation behind these diseases and FoxO1-related drug discoveries.

scholarly journals PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Marcello Dallio ◽  
Mario Masarone ◽  
Mario Romeo ◽  
Concetta Tuccillo ◽  
Filomena Morisco ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Controlled Trial ◽  
Daily Intake ◽  
Therapeutic Regimen ◽  
Thiobarbituric Acid Reactive Substance ◽  
Wild Type ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Introduction: PNPLA3, TM6SF2, and MBOAT7 genes play a crucial role in non-alcoholic fatty liver disease (NAFLD) development and worsening. However, few data are available on their treatment response influence. The aim of this trial is to explore the effect derived from silybin-phospholipids complex (303 mg of silybin-phospholipids complex, 10 μg of vitamin D, and 15 mg of vitamin E twice a day for 6 months) oral administration in NAFLD patients carrying PNPLA3-rs738409, TM6SF2-rs58542926, or MBOAT7-rs641738 genetic variants.Materials and Methods: In all, 92 biopsy-proven NAFLD patients were grouped in 30 NAFLD wild type controls, 30 wild type treated patients, and 32 mutated treated ones. We assessed glycemia (FPG), insulinemia, HOMA-IR, aspartate and alanine aminotransferases (AST, ALT), C-reactive protein (CRP), thiobarbituric acid reactive substance (TBARS), stiffness, controlled attenuation parameter (CAP), dietary daily intake, and physical activity at baseline and end of treatment.Results: The wild-type treated group showed a significant improvement of FPG, insulinemia, HOMA-IR, ALT, CRP, and TBARS (p < 0.05), whereas no improvements were recorded in the other two study groups. NAFLD wild type treated patients showed higher possibilities of useful therapeutic outcome (p < 0.01), obtained from the prescribed therapeutic regimen, independently from age, sex, comorbidities, medications, CAP, and stiffness in comparison to the mutated group.Discussion: The assessed mutations are independently associated with no response to a silybin-based therapeutic regimen and could be considered as useful predictive markers in this context.Clinical Trial Registry Number:www.ClinicalTrials.gov, identifier: NCT04640324.

scholarly journals The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease: a brief review

2018 ◽  
Vol 41 (6) ◽  
pp. 394-405 ◽  
Author(s):  
Luciana M. A. Borém ◽  
João F. R. Neto ◽  
Igor V. Brandi ◽  
Deborah F Lelis ◽  
Sergio H. S. Santos
Keyword(s):  
Liver Disease ◽  
Angiotensin Ii ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Receptor Blocker ◽  
Type I ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1883
Author(s):  
Biljana Atanasovska ◽  
Sander S. Rensen ◽  
Glenn Marsman ◽  
Ronit Shiri-Sverdlov ◽  
Sebo Withoff ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Hepg2 Cells ◽  
Fatty Liver Disease ◽  
Human Liver ◽  
Target Genes ◽  
Alcoholic Fatty Liver ◽  
Non Coding Rnas ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation.

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