Regulation of systemic metabolism by tissue-resident immune cell circuits DOI Creative Commons
Joey H. Li, Matthew R. Hepworth, Timothy E. O’Sullivan

et al.

Immunity, Journal Year: 2023, Volume and Issue: 56(6), P. 1168 - 1186

Published: June 1, 2023

Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells form functional cell circuits with structural cells. Within these circuits, integrate cues from dietary contents commensal microbes in addition to endocrine neuronal signals present the microenvironment regulate metabolism. These can become dysregulated during inflammation overnutrition, contributing diseases. Here, we review evidence describing key cellular networks within between liver, gastrointestinal tract, adipose control systemic metabolism how certain We also identify open questions field potential enhance our understanding of health disease.

Language: Английский

Hepatic fibrosis 2022: Unmet needs and a blueprint for the future DOI
Scott L. Friedman, Massimo Pinzani

Hepatology, Journal Year: 2021, Volume and Issue: 75(2), P. 473 - 488

Published: Dec. 19, 2021

Abstract Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to expectation effective antifibrotic drugs, yet none been approved. Thus, an assessment field is timely, clarify priorities accelerate progress. Here, we highlight successes date but, more importantly, identify gaps unmet needs, both experimentally clinically. These include need better define cell–cell interactions etiology‐specific elements fibrogenesis their link disease‐specific drivers portal hypertension. Success in treating viral hepatitis revealed remarkable capacity liver degrade scar reversing fibrosis, know little mechanisms underlying this response. there exigent cellular molecular regression order for therapeutics mimic liver’s endogenous capacity. Better refined predictive vitro animal models will hasten drug development. From a perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate supplant biopsy. More urgently, digital pathology methods that leverage machine learning artificial intelligence must be validated capture prognostic information from biopsies quantify response therapies. For treatment NASH, orthogonal approaches integrate genetic, clinical, pathological data sets may yield treatments specific subphenotypes disease. Collectively, these other advances strengthen streamline trials histologic responses outcomes.

Language: Английский

Citations

289
Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) DOI
Shuang Wang, Scott L. Friedman

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(716)

Published: Oct. 4, 2023

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses global health threat because its potential to progress advanced fibrosis, leading cirrhosis and cancer. Recent advances in single-cell methodologies, refined models, genetic epigenetic insights have provided nuanced understanding MASH fibrogenesis, with substantial cellular heterogeneity livers providing potentially targetable cell-cell interactions behavior. Unlike mechanisms underlying fibrosis regression are still inadequately understood, although antifibrotic targets been recently identified. A treatment framework could lead noninvasive assessment targeted therapies preserve hepatocellular function restore the liver’s architectural integrity.

Language: Английский

Citations

55
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
Epithelial–mesenchymal transition in tissue repair and degeneration DOI
Khalil Kass Youssef, M. Ángela Nieto

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 720 - 739

Published: April 29, 2024

Language: Английский

Citations

25
Vicious Cycle‐Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis DOI
Lingfeng Zhang,

Wen‐Qi Deng,

Qing‐Wen Huang

et al.

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(16)

Published: Jan. 9, 2024

During liver fibrogenesis, the reciprocal crosstalk among capillarized sinusoidal endothelial cells (LSECs), activated hepatic stellate (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating disease condition weakening therapeutic effect. Limited by malignant cellular interactions, previous single-cell centric treatment approaches show unsatisfactory efficacy fail to meet clinical demand. Herein, cycle-breaking strategy is proposed target repair pathological separately terminate progression of fibrosis. Chondroitin sulfate-modified vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed efficiently normalize fenestrae phenotype LSECs restore HSCs quiescent state inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified silybin-loaded (GA-NPs/SIB) prepared function relieving oxidative stress. The results successful interruption cycle as well distinct fibrosis resolution in two animal models through multiregulation cells. This work not only highlights significance modulating but also provides promising avenue for developing antifibrotic regimens.

Language: Английский

Citations

17
A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis DOI Creative Commons
Anne Loft, Søren Fisker Schmidt, Giorgio Caratti

et al.

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(3), P. 473 - 486.e9

Published: Feb. 3, 2022

Language: Английский

Citations

58
Loss of liver function in chronic liver disease: An identity crisis DOI Creative Commons
Carmen Berasain, María Arechederra, Josepmaria Argemì

et al.

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 78(2), P. 401 - 414

Published: Sept. 15, 2022

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes proteins needed to perform complex metabolic secretory functions mature liver. Transient hepatocellular dedifferentiation can occur as part regenerative mechanisms triggered in response acute liver injury. However, persistent downregulation key genes now accepted a strong determinant organ dysfunction chronic disease, major global health burden. Therefore, identification core factors regulators that preserve phenotype, thorough understanding how these networks become disrupted diseased hepatocytes, high clinical relevance. In this context, we review players differentiation discuss detail critical such HNF4α, whose impairment mediates breakdown function. Moreover, present compelling experimental evidence demonstrating restoration factor expression chronically injured reset identity, improve function ameliorate structural abnormalities. The possibility correcting phenotype severely damaged malfunctional livers may reveal new therapeutic opportunities for individuals cirrhosis advanced disease.

Language: Английский

Citations

55
Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis DOI
Yang Xiao, Kirill Batmanov, Wenxiang Hu

et al.

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(682)

Published: Feb. 8, 2023

Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics characterize all major cell types during NASH development in mice humans. The bifurcation of hepatocyte trajectory with progression was conserved between At the fatty (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at subset enriched signatures adhesion migration, were mainly demarcated by receptor tyrosine kinase ephrin type B 2 (EphB2). EphB2, acting as downstream effector Notch signaling hepatocytes, sufficient induce cell-autonomous inflammation. Knockdown Ephb2 ameliorated inflammation fibrosis mouse model NASH. Thus, EphB2-expressing contribute may serve potential target.

Language: Английский

Citations

35
The role of N-glycosylation modification in the pathogenesis of liver cancer DOI Creative Commons

Mengyu Hu,

Rui Zhang,

Jiaren Yang

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(3)

Published: March 29, 2023

Abstract N-glycosylation is one of the most common types protein modifications and it plays a vital role in normal physiological processes. However, aberrant N-glycan are closely associated with pathogenesis diverse diseases, including processes such as malignant transformation tumor progression. It known that conformation glycoproteins altered during different stages hepatocarcinogenesis. Characterizing heterogeneity biological functions glycans liver cancer patients will facilitate deeper understanding molecular mechanisms injury In this article, we review hepatocarcinogenesis, focusing on epithelial-mesenchymal transition, extracellular matrix changes, microenvironment formation. We highlight its potential applications treatment or diagnosis cancer.

Language: Английский

Citations

27
Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma DOI Creative Commons
Stephanie Talamantes,

Michela Lisjak,

Eduardo Hideo Gilglioni

et al.

JHEP Reports, Journal Year: 2023, Volume and Issue: 5(9), P. 100811 - 100811

Published: June 9, 2023

Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into molecular mechanisms that underlie role steatosis, hyperinsulinemia hepatic inflammation in HCC progression. We focus on recent findings linking intracellular pathways transcription can trigger reprogramming cells. In addition, we highlight enzymes dysregulated metabolic activity consequent dysfunctional signalling. Finally, discuss potential uses challenges novel therapeutic strategies to prevent treat NAFLD/T2D-associated HCC.

Language: Английский

Citations

26