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Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice.

ABSTRACT: Osteopontin (OPN), a multifunctional cytokine that controls liver glycerolipid metabolism, is involved in activation and proliferation of several liver cell types during regeneration, a condition of high metabolic demands. Here we investigated the role of OPN in modulating the liver lipidome during regeneration after partial-hepatectomy (PH) and the impact that atorvastatin treatment has over regeneration in OPN knockout (KO) mice. The results showed that OPN deficiency leads to remodeling of phosphatidylcholine and triacylglycerol (TG) species primarily during the first 24?h after PH, with minimal effects on regeneration. Changes in the quiescent liver lipidome in OPN-KO mice included TG enrichment with linoleic acid and were associated with higher lysosome TG-hydrolase activity that maintained 24?h after PH but increased in WT mice. OPN-KO mice showed increased beta-oxidation 24?h after PH with less body weight loss. In OPN-KO mice, atorvastatin treatment induced changes in the lipidome 24?h after PH and improved liver regeneration while no effect was observed 48?h post-PH. These results suggest that increased dietary-lipid uptake in OPN-KO mice provides the metabolic precursors required for regeneration 24?h and 48?h after PH. However, atorvastatin treatment offers a new metabolic program that improves early regeneration when OPN is deficient.

SUBMITTER: Nunez-Garcia M

PROVIDER: S-EPMC6168585 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice.

Nuñez-Garcia Maitane M Gomez-Santos Beatriz B Saenz de Urturi Diego D Mestre Daniela D Gonzalez-Romero Francisco F Buque Xabier X Gutiérrez-de Juan Virginia V Martinez-Chantar María Luz ML Syn Wing-Kin WK Fresnedo Olatz O Aspichueta Patricia P

Scientific reports 20181002 1

Osteopontin (OPN), a multifunctional cytokine that controls liver glycerolipid metabolism, is involved in activation and proliferation of several liver cell types during regeneration, a condition of high metabolic demands. Here we investigated the role of OPN in modulating the liver lipidome during regeneration after partial-hepatectomy (PH) and the impact that atorvastatin treatment has over regeneration in OPN knockout (KO) mice. The results showed that OPN deficiency leads to remodeling of ph ...[more]

PMID: 30279550

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Project description:Alveolar echinococcosis (AE) is caused by the larval stage of echinococcus multilocularis (E. multilocularis), and hepatectomy is the main modality in hepatic AE patients. Liver regeneration after partial hepatectomy (PHx) in such patients is challenging, and further investigation is needed. Thus far, knowledge regarding the possible impact of E. multilocularis on liver regeneration after PHx is limited. Herein, a subcutaneous infection model of E. multilocularis was developed in C57 BL/6 mice, and after 3 months, PHx was performed. Plasma and liver samples were harvested under inhalational isofluorane (2%) anaesthesia at designated post-PHx time points (0, 24, 48, 96 and 168 h). The parameters included the future remnant liver/body weight ratio (FLR/BW), liver function tests (AST and ALT) and related cytokines (TNF-α, IL-6, Factor V, HMGB1, TGF-β, TSP-1, and TLR4) and proteins (MyD88 and STAT3). To assess the proliferation intensity of hepatocytes, BrdU, Ki67 and PAS staining were carried out in regenerated liver tissue. The FLR/BW in the infected group from 48 h after surgery was lower than that in the control group. The BrdU positive hepatocyte proportions reached their peak at 48 h in the control group and 96 h in the infected group and then gradually decreased. During the first 48 h after surgery, both the AST and ALT levels in the infected group were lower; however, these levels were altered from 96 h after surgery. In the infected group, the concentrations and mRNA expression levels of the pre-inflammatory cytokines TNF-α and IL-6 demonstrated a delayed peak. Moreover, post-operatively, the TGF-β and TSP-1 levels showed high levels in the infected group at each different time-point compared to those in the control group; however, high levels of TGF-β were observed at 96 h in the control group. The MyD88 and STAT3 protein expression levels in the infected group were markedly higher than those in the control group 96 h after surgery. Delayed liver regeneration after PHx was observed in the C57 BL/6 mice with the subcutaneous infection of E. multilocularis in the current study. This phenomenon could be partially explained by the alteration in the pro-inflammatory cytokines in the immunotolerant milieu induced by chronic E. multilocularis infection.

Dataset Information

Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice.

Publications

Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice.

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