Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress DOI Creative Commons

Sabira Mohammed,

Evan H. Nicklas,

Nidheesh Thadathil

et al.

Free Radical Biology and Medicine, Journal Year: 2021, Volume and Issue: 164, P. 315 - 328

Published: Jan. 12, 2021

Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1-/- or Sod1KO mice) have increased oxidative stress, show accelerated aging and develop spontaneous hepatocellular carcinoma (HCC) with age. Similar to humans, HCC development mice progresses from non-alcoholic fatty liver disease (NAFLD) steatohepatitis (NASH) fibrosis, which eventually HCC. Oxidative stress plays a role NAFLD NASH progression, inflammation is main mechanism that drives progression fibrosis. Because necroptosis major source of inflammation, we tested hypothesis fibrosis mice. Phosphorylation MLKL (P-MLKL), well-accepted marker necroptosis, expression protein were significantly livers compared wild type (WT) indicating necroptosis. Similarly, phosphorylation RIPK3 levels also increased. Markers pro-inflammatory M1 macrophages, NLRP3 inflammasome, transcript cytokines chemokines, e.g., TNFα, IL-6, IL-1β, Ccl2 are associated human NASH, Expression enzymes heat shock proteins, markers oncogenic transcription factor STAT3 upregulated autophagy was downregulated Short term treatment necrostatin-1s (Nec-1s), inhibitor, reversed these conditions. Our data for first time necroptosis-mediated contributes mouse model aging, exhibits progressive development.

Language: Английский

Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH DOI Creative Commons
Tim Hendrikx, Florentina Porsch, Máté G. Kiss

et al.

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 77(5), P. 1373 - 1385

Published: June 21, 2022

Language: Английский

Citations

121
A Systematic Review of Animal Models of NAFLD Finds High‐Fat, High‐Fructose Diets Most Closely Resemble Human NAFLD DOI
Yu Ri Im, Harriet Hunter, Dana de Gracia Hahn

et al.

Hepatology, Journal Year: 2021, Volume and Issue: 74(4), P. 1884 - 1901

Published: May 11, 2021

Background and Aims Animal models of human disease are a key component translational hepatology research, yet there is no consensus on which model optimal for NAFLD. Approach Results We generated database 3,920 rodent Study designs were highly heterogeneous, therefore, few had been cited more than once. Analysis genetic supported the current evidence role adipose dysfunction suggested innate immunity in progression identified that high‐fat, high‐fructose diets most closely recapitulate phenotype There was substantial variability nomenclature animal models: terminology specialist needed. More broadly, this analysis demonstrates preclinical study design, has wider implications reproducibility vivo experiments both field beyond. Conclusions This systematic provides framework phenotypic assessment NAFLD highlights need increased standardization replication.

Language: Английский

Citations

120
Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma DOI Creative Commons
Yeming Yang,

Jingshu Cai,

Xue Yang

et al.

Molecular Therapy, Journal Year: 2022, Volume and Issue: 30(6), P. 2342 - 2353

Published: Feb. 19, 2022

Type 2 diabetes mellitus (DM2) is associated closely with non-alcoholic fatty liver disease (NAFLD) by affecting lipid metabolism, which may lead to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). N6-methyladenosine (m6A) RNA methylation an important epigenetic regulation for gene expression related HCC development. We developed a new NAFLD model oriented from DM2 mouse, spontaneously progressed histological features of NASH, high incidence. By sequencing, protein methylated immunoprecipitation (MeRIP)-qPCR analysis, we found that enhanced ACLY SCD1 in this human samples was due excessive m6A modification, but not elevation mature SREBP1. Moreover, targeting METTL3/14 vitro increases level as well triglyceride cholesterol production accumulation droplets. sequencing analysis revealed overexpressed METTL14 binds mRNA alters their pattern. Our findings demonstrate mouse provides study platform DM2-related reveals unique epitranscriptional regulating mechanism metabolism via m6A-modified SCD1.

Language: Английский

Citations

116
Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development DOI Creative Commons
Xiaochen Wang,

Qifeng He,

Chuanli Zhou

et al.

Immunity, Journal Year: 2022, Volume and Issue: 56(1), P. 58 - 77.e11

Published: Dec. 14, 2022

Language: Английский

Citations

116
UCP1 governs liver extracellular succinate and inflammatory pathogenesis DOI
Evanna L. Mills, Cathal Harmon,

Mark P. Jedrychowski

et al.

Nature Metabolism, Journal Year: 2021, Volume and Issue: 3(5), P. 604 - 617

Published: May 17, 2021

Language: Английский

Citations

115
A researcher’s guide to preclinical mouse NASH models DOI
Suchira Gallage, Jose Efren Barragan Avila, Pierluigi Ramadori

et al.

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(12), P. 1632 - 1649

Published: Dec. 20, 2022

Language: Английский

Citations

107
“Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis DOI Creative Commons
Mark A. Febbraio, Michael Karin

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(12), P. 2316 - 2328

Published: Oct. 8, 2021

Language: Английский

Citations

105
Epigenetics in NAFLD/NASH: Targets and therapy DOI
Nalini Sodum, Gautam Kumar, Sree Lalitha Bojja

et al.

Pharmacological Research, Journal Year: 2021, Volume and Issue: 167, P. 105484 - 105484

Published: March 24, 2021

Language: Английский

Citations

104
Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver DOI Creative Commons
Weiguo Fan, Kolade Adebowale, Lóránd Váncza

et al.

Nature, Journal Year: 2024, Volume and Issue: 626(7999), P. 635 - 642

Published: Jan. 31, 2024

Abstract Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development 1,2 , and increased stiffness known promote HCC progression cirrhotic conditions 3,4 . characterized by an accumulation of advanced glycation end-products (AGEs) the ECM; however, how this affects non-cirrhotic unclear. Here we find that, patients animal models, AGEs changes collagen architecture enhance ECM viscoelasticity, with greater viscous dissipation faster stress relaxation, but not stiffness. High viscoelasticity combined oncogenic β-catenin signalling induction, whereas inhibiting AGE production, reconstituting clearance receptor AGER1 or breaking AGE-mediated cross-links reduces growth. Matrix analysis computational modelling demonstrate that lower interconnectivity AGE-bundled matrix, marked shorter fibre length heterogeneity, enhances viscoelasticity. Mechanistically, studies 3D cell cultures show enhanced promotes proliferation invasion through integrin-β1–tensin-1–YAP mechanotransductive pathway. These results reveal structural can vivo, independent

Language: Английский

Citations

87
Molecular mechanisms in MASLD/MASH-related HCC DOI
Xiaobo Wang, Liang Zhang, Bingning Dong

et al.

Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 13, 2024

Liver cancer is the third leading cause of cancer-related deaths and ranks as sixth most prevalent type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, its more severe manifestation, NASH steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% population. The increased prevalence disease MASH parallel to increasing rates obesity-associated diseases, including 2 diabetes, insulin resistance, fatty diseases. can progress MASH-related HCC (MASH-HCC) in about 2% cases each year, influenced by various factors such genetic mutations, carcinogen exposure, immune microenvironment, microbiome. MASH-HCC exhibits distinct molecular characteristics compared other causes affects both men women equally. management early intermediate-stage typically involves surgery locoregional therapies, while advanced treated with systemic anti-angiogenic therapies checkpoint inhibitors. In this comprehensive review, we consolidate previous research findings also providing current insights into intricate processes underlying development. We delve MASH-HCC-associated variations somatic progression models, multiomics analysis, immunological microenvironmental impacts, discuss targeted/combined overcome evasion biomarkers recognize treatment responders. By furthering our comprehension mechanisms MASH-HCC, goal catalyze advancement potent strategies, ultimately enhanced patient outcomes.

Language: Английский

Citations

43