Liver regeneration: Cellular origin and molecular mechanisms

Huang, Ru Chih C.; Zhang, Xin; Gracia‐Sancho, Jordi; Xie, Wei-Fen

doi:10.1111/liv.15174

Cited by 24 publications

(28 citation statements)

References 107 publications

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“…Some patients have the alternation of normal and abnormal liver function, indicating that on the one hand, the liver is damaged and on the other hand, it has strong self-healing function. 17 However, the proportion of patients with abnormal liver function detected at least once from T1 to T4 is amazing, therefore, long-term dynamic monitoring of patients’ liver function status is necessary.…”

Section: Discussionmentioning

confidence: 99%

Changes in Serum Liver Function for Patients with COVID-19: A 1-Year Follow-Up Study

Zhu¹,

Wang²,

Du³

et al. 2022

IDR

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Objective Abnormal liver function and liver injury related to COVID-19 during hospitalization has received widespread attention. However, the long-term observation of patients’ liver functions after discharge has not been investigated. This study intends to analyze the abnormal liver function in patients one year after they are discharged. Methods Serum liver function tests were analyzed for the first time immediately after hospitalization (T1), before discharge (T2), a median of 14.0 (14.0, 15.0) days after discharge (T3) and 1 year (356.0 (347.8, 367.0) days) after discharge (T4). Patients with at least one serum parameter (ALT, AST, ALP, GGT and TB) exceeding the upper limit of reference range were defined as having abnormal liver function. Results For the 118 COVID-19 patients with a median follow-up time of 376.0 (71.5, 385.3) days from onset to the end of the follow-up after discharge, the proportion with abnormal liver function in T1, T2, T3 and T4 were 32.2%, 45.8%, 54.8% and 28.8%, respectively. The proportion of patients with at least once abnormal liver function detected from T1 to T2, T1 to T3, T1 to T4 was 60.2%, 77.4% and 88.9%, respectively. From T1 to T4, the ALT, AST, GGT and BMI at admission were significantly higher in the patients with persistently abnormal liver function than in the patients with persistently normal liver function. Abnormal liver function was mainly manifested in the elevation of GGT and TB levels. Multivariate logistics regression analysis showed that age and gender-adjusted ALT (odds ratio [OR]=2.041, 95% confidence interval [CI]: 1.170–3.561, P =0.012) at admission was a risk factor for abnormal liver function in the T4 stage. Conclusion Abnormal liver function in patients with COVID-19 can persist from admission to one year after discharge, and therefore, the long-term dynamic monitoring of liver function in patients with COVID-19 is necessary.

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Section: Discussionmentioning

confidence: 99%

Changes in Serum Liver Function for Patients with COVID-19: A 1-Year Follow-Up Study

Zhu¹,

Wang²,

Du³

et al. 2022

IDR

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“…Overall, it can be concluded that increased oxidative stress and the resulting accumulation of carbonylated proteins may be a result of defective autophagosomal processing during human and murine cholestatic liver disease. The specific location of the affected hepatocytes (periportal hepatocytes) in human and murine cholestasis is of particular interest in that these cells have been shown to be capable of trans-differentiation into biliary epithelium that may be involved in the regeneration and healing of cholestatic bile duct injury [ 19 , 20 , 52 ], as seen in PSC. This raises the possibility that defective autophagy as a result of oxidative stress may render these cells incapable of transdifferentiation, thus perpetuating intrahepatic bile ductular injury, and that reduction of oxidative stress may promote autophagy of the periportal hepatocytes allowing for transdifferentiation and bile duct healing.…”

Section: Discussionmentioning

confidence: 99%

“…The resultant accumulation of highly reactive lipid aldehydes can modify proteins through interactions with critical cysteine, lysine and histidine residues, thus impairing function [ 18 ]. During cholestatic liver injury, periportal hepatocytes undergo hepatocyte to cholangiocyte transdifferentiation [ 19 , 20 ]. We have shown that carbonylation and oxidative injury is increased in periportal hepatocytes in liver from patients diagnosed with PSC [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease

et al. 2022

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Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12, Lamp1, Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His123, Cys128, His174, His181, Lys238, Cys290, His340, Lys341 and His385. These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction.

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“…Indeed, several models have confirmed that, in the case of impaired hepatocyte regeneration, a response is established that significantly increases the percentage of hepatocytes derived from cholangiocytes, which enables the regenerative process to be correctly completed [ 114 ]. The intrinsic plasticity that hepatocytes and cholangiocytes display facilitates the trans-differentiation process, so that one cell type can make up for the lack of the other and vice versa [ 115 , 116 , 117 ].…”

Section: Molecular Mechanisms Of Liver Regenerationmentioning

confidence: 99%

Liver Regeneration and Immunity: A Tale to Tell

Di-Iacovo

Pieroni

Piobbico

et al. 2023

IJMS

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The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.

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Liver regeneration: Cellular origin and molecular mechanisms

Cited by 24 publications

References 107 publications

Changes in Serum Liver Function for Patients with COVID-19: A 1-Year Follow-Up Study

Changes in Serum Liver Function for Patients with COVID-19: A 1-Year Follow-Up Study

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease

Liver Regeneration and Immunity: A Tale to Tell

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