Maladaptive regeneration — the reawakening of developmental pathways in NASH and fibrosis

Zhu, Changyu; Tabas, Ira; Schwabe, Robert F.; Pajvani, Utpal B.

doi:10.1038/s41575-020-00365-6

Cited by 78 publications

(72 citation statements)

References 174 publications

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“…Developmental pathways including Notch, Hedgehog and YAP–TAZ are persistently activated to cope with the chronic insult. As a result, crosstalk of hepatocytes-macrophages-hepatic stellate cells and activation of resident Kupffer cells lead to inflammatory and fibrogenic responses[ 50 ].…”

Section: Progression and Outcomes Of Chb With Nafldmentioning

confidence: 99%

Chronic hepatitis B infection with concomitant hepatic steatosis: Current evidence and opinion

Shi¹,

Yang²,

Fan³

2021

WJG

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With the increasing incidence of obesity and metabolic syndrome worldwide, concomitant nonalcoholic fatty liver disease (NAFLD) in patients with chronic hepatitis B (CHB) has become highly prevalent. The risk of dual etiologies, outcome, and mechanism of CHB with concomitant NAFLD have not been fully characterized. In this review, we assessed the overlapping prevalence of metabolic disorders and CHB, assessed the risk of advanced fibrosis/hepatocellular carcinoma in CHB patients concomitant with NAFLD, and discussed the remaining clinical issues to be addressed in the outcome of such patients. We also explored the possible roles of hepatitis B virus in the development of steatosis and discussed difficultiesof histological evaluation. For CHB patients, it is important to address concomitant NAFLD through lifestyle management and disease screening to achieve better prognoses. The assessment of progressive changes and novel therapies for CHB patients concomitant with NAFLD deserve further research.

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Section: Progression and Outcomes Of Chb With Nafldmentioning

confidence: 99%

Chronic hepatitis B infection with concomitant hepatic steatosis: Current evidence and opinion

Shi¹,

Yang²,

Fan³

2021

WJG

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“…The canonical Hedgehog (Hh) pathway is a conserved, highly complex signaling cascade, with many players and intricate regulation [98]. Patient and mouse data have shown that hepatic fibrosis is associated with Hedgehog activation [99]. It can be simplified into four fundamental components: (i) the ligand Hedgehog, (ii) the receptor Patched (Patch), (iii) the signal transducer Smoothened (Smo), and (iv) the effector transcription factor, Gli.…”

Section: Hedgehog Signalingmentioning

confidence: 99%

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

et al. 2021

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Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

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“…Although typically expressed at low and spatially restricted levels in healthy mature liver, developmental pathway reactivation is a hallmark of NAFLD/NASH progression 18 . Reactivation and/or altered zonal distribution of morphogenic signals during lipotoxic stress may drive ensuing liver inflammation and fibrosis 18 .…”

Section: Developmental Pathways As Determinants Of Nafld Zonationmentioning

confidence: 99%

Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes

Steinman

Salomao

Pajvani

2021

Liver International

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Non‐alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β‐Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient‐specific activation of these pathways may explain the variability in clinical presentation, and the zone‐specific response observed in clinical trials.

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Maladaptive regeneration — the reawakening of developmental pathways in NASH and fibrosis

Cited by 78 publications

References 174 publications

Chronic hepatitis B infection with concomitant hepatic steatosis: Current evidence and opinion

Chronic hepatitis B infection with concomitant hepatic steatosis: Current evidence and opinion

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

Zonation in NASH – A key paradigm for understanding pathophysiology and clinical outcomes

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