Metabolic hallmarks of liver regeneration

Aminian, Mahdi; Lotfinia, Majid; Gramignoli, Roberto; Najimi, Mustapha; Vosough, Massoud

doi:10.1016/j.tem.2021.06.002

Cited by 35 publications

(21 citation statements)

References 93 publications

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“…Metabolic processes are fundamental for organismal growth and development, and are required for the coordinated regulation of regeneration 30 , 31 . Indeed, we found that the convergent changes of metabolism-related genes across species were more prominent than that of global gene expression between samples with differential regeneration capacities (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Liu

Geng

et al. 2022

Cell Discov

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Regenerative capacity declines throughout evolution and with age. In this study, we asked whether metabolic programs underlying regenerative capability might be conserved across species, and if so, whether such metabolic drivers might be harnessed to promote tissue repair. To this end, we conducted metabolomic analyses in two vertebrate organ regeneration models: the axolotl limb blastema and antler stem cells. To further reveal why young individuals have higher regenerative capacity than the elderly, we also constructed metabolic profiles for primate juvenile and aged tissues, as well as young and aged human stem cells. In joint analyses, we uncovered that active pyrimidine metabolism and fatty acid metabolism correlated with higher regenerative capacity. Furthermore, we identified a set of regeneration-related metabolite effectors conserved across species. One such metabolite is uridine, a pyrimidine nucleoside, which can rejuvenate aged human stem cells and promote regeneration of various tissues in vivo. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

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Section: Resultsmentioning

confidence: 99%

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Liu

Geng

et al. 2022

Cell Discov

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“…3C ). Since transient steatosis is a metabolic hallmark of the early phase of liver regeneration [ 18 ], we performed oil red O staining and found that hepatic triglyceride levels were significantly decreased in β 2 ARKO mouse livers compared with WT mice (Fig. S1A ).…”

Section: Resultsmentioning

confidence: 99%

β2-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met

Tao

Chen

et al. 2022

Cell Death Dis

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The β2-adrenergic receptor (β2AR) is a G protein-coupled receptor (GPCR) that mediates the majority of cellular responses to external stimuli. Aberrant expression of β2AR results in various pathophysiological disorders, including tumorigenesis, but little is known about its role in liver regeneration. This study aims to investigate the impact and the underlying mechanism of β2AR in liver regeneration. Here, we found that β2AR was upregulated during liver regeneration induced by 70% PH. Deletion of β2AR in mice resulted in 62% mortality 2 days post-PH, decreased proliferative marker expression and impaired liver function throughout regeneration. Moreover, AAV8-mediated overexpression of β2AR in hepatocytes accelerated the regeneration process and increased target gene expression. Mechanistically, β2AR recruited G-protein-coupled receptor kinase 2 (GRK2) to the membrane and then formed a complex with c-met to transactivate c-met signaling, which triggered downstream extracellular regulated protein kinase (ERK) signaling activation and nuclear translocation. Inhibition of c-met with SU11274 or ERK with U0126 decreased β2AR overexpression-induced hepatocyte proliferation. Our findings revealed that β2AR might act as a critical mediator regulating liver regeneration by crosstalk with c-met and activation of ERK signaling.

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“…HNF4 α is a liver-enriched TF that plays important roles including in gluconeogenesis and lipid metabolism [ 43 , 44 ]. Numerous studies have shown that HNF4α expression is reduced in HCC patients in a stage dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Conjugated Linoleic Acid Treatment Attenuates Cancerous features in Hepatocellular Carcinoma Cells

Miri-Lavasani

Torabi

Aminian

et al. 2022

Stem Cells International

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Background. A growing number of hepatocellular carcinoma (HCC), and recurrence frequency recently have drawn researchers’ attention to alternative approaches. The concept of differentiation therapies (DT) relies on inducing differentiation in HCC cells in order to inhibit recurrence and metastasis. Hepatocyte nuclear factor 4 alpha (HNF4α) is the key hepatogenesis transcription factor and its upregulation may decrease the invasiveness of cancerous cells by suppressing epithelial-mesenchymal transition (EMT). This study aimed to evaluate the effect of conjugated linoleic acid (CLA) treatment, natural ligand of HNF4α, on the proliferation, migration, and invasion capacities of HCC cells in vitro. Materials and Method. Sk-Hep-1 and Hep-3B cells were treated with different doses of CLA or BIM5078 [1-(2 ′ -chloro-5 ′ -nitrobenzenesulfonyl)−2-methylbenzimidazole], an HNF4α antagonist. The expression levels of HNF4a and EMT related genes were evaluated and associated to hepatocytic functionalities, migration, and colony formation capacities, as well as to viability and proliferation rate of HCC cells. Results. In both HCC lines, CLA treatment induced HNF4α expression in parallel to significantly decreased EMT marker levels, migration, colony formation capacity, and proliferation rate, whereas BIM5078 treatment resulted in the opposite effects. Moreover, CLA supplementation also upregulated ALB, ZO1, and HNF4α proteins as well as glycogen storage capacity in the treated HCC cells. Conclusion. CLA treatment can induce a remarkable hepatocytic differentiation in HCC cells and attenuates cancerous features. This could be as a result of HNF4a induction and EMT inhibition.

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Metabolic hallmarks of liver regeneration

Cited by 35 publications

References 93 publications

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

β2-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met

Conjugated Linoleic Acid Treatment Attenuates Cancerous features in Hepatocellular Carcinoma Cells

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