Dysfunction of liver regeneration in aged liver after partial hepatectomy

Enkhbold, Chinbold; Morine, Yuji; Utsunomiya, Tohru; Imura, Satoru; Ikemoto, Tetsuya; Arakawa, Yusuke; Saito, Yu; Yamada, Shinichiro; Ishikawa, Daichi

doi:10.1111/jgh.12930

Cited by 55 publications

(58 citation statements)

References 38 publications

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“…The administration of peretinoin weakly but significantly increased the expression of LC3B-II. At 68 weeks, the expression of LC3B-II in the liver of control LF diet mice increased as reported previously; [14] however, its expression did not increase in the liver of Ath+HF diet mice. The administration of peretinoin restored the expression of LC3B-II (Figure 4A and 4B).…”

Section: Resultssupporting

confidence: 84%

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Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet

et al. 2017

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The pathogenesis of non-alcoholic steatohepatitis (NASH) is still unclear and the prevention of the development of hepatocellular carcinoma (HCC) has not been established. We established an atherogenic and high-fat diet mouse model that develops hepatic steatosis, inflammation, fibrosis, and liver tumors at a high frequency. Using two NASH-HCC mouse models, we showed that peretinoin, an acyclic retinoid, significantly improved liver histology and reduced the incidence of liver tumors. Interestingly, we found that peretinoin induced autophagy in the liver of mice, which was characterized by the increased co-localized expression of microtubule-associated protein light chain 3B-II and lysosome-associated membrane protein 2, and increased autophagosome formation and autophagy flux in the liver. These findings were confirmed using primary mouse hepatocytes. Among representative autophagy pathways, the autophagy related (Atg) 5-Atg12-Atg16L1 pathway was impaired; especially, Atg16L1 was repressed at both the mRNA and protein level. Decreased Atg16L1 mRNA expression was also found in the liver of patients with NASH according to disease progression. Promoter analysis revealed that peretinoin activated the promoter of Atg16L1 by increasing the expression of CCAAT/enhancer-binding-protein-alpha. Interestingly, Atg16L1 overexpression in HepG2 cells inhibited palmitate-induced NF-kB activation and interleukin-6-induced STAT3 activation. We showed that Atg16L1 induced the de-phosphorylation of Gp130, a receptor subunit of interleukin-6 family cytokines, which subsequently repressed phosphorylated-STAT3 (Tyr705) levels, and this process might be independent of autophagy function. Thus, peretinoin prevents the progression of NASH and the development of HCC through activating the autophagy pathway by increased Atg16L1 expression, which is an essential regulator of autophagy and anti-inflammatory proteins.

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Section: Resultssupporting

confidence: 84%

“…The impaired autophagy was restored by the administration of peretinoin (Figure 4 and Supplemental Figure 2), and this finding was more obvious in older mice, which would be associated with the increased autophagy observed in the liver of normal aged mice without tumors. [14]…”

Section: Discussionmentioning

confidence: 99%

Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet

et al. 2017

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“…It is reported that compared with young mice, old mice showed a significantly lower expression of hepatocyte growth factor, cMet, cyclin D1, cyclin A2, and PCNA as well as a markedly elevated level of caspase-3 after partial hepatectomy 10 . In addition, Zhang and colleagues indicate that intravenous injection of IL-22 could enhance liver regeneration in mice with Con A-induced hepatitis after partial hepatectomy by augmentation of PCNA and cyclin D1 levels 14 .…”

Section: Discussionmentioning

confidence: 99%

“…The loss of regenerative capacity is the most dramatic age-associated alteration in liver tissue after surgical resection or chemical injury 10, 11 . Enkhbold et al .…”

Section: Introductionmentioning

confidence: 99%

“…Enkhbold et al . indicate that impaired liver regeneration in mice is due to aging, which is expressed by an increase of autophagy and apoptosis after partial hepatectomy 10 . In addition, the reduced response to oxidative stress and decreased expression of growth-regulatory factors also contribute to reduced hepatic regenerative capacity and further increase susceptibility to certain liver diseases among the aged 12 .…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice

Huang

Chen

Liu³

et al. 2017

Sci Rep

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Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66shc in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66shc. Aged mice were administrated resveratrol (30 mg/kg orally) seven times at an interval of 12 h before a single intravenous injection of Con A (20 mg/kg). Results showed that the cytokines, TNF-α, IL-6, IFN-γ, and MCP-1, as well as infiltration of macrophages, neutrophils, and T lymphocytes in liver were dramatically enhanced in the mice given only Con A. The aged mouse livers showed markedly raised oxidative stress and cell apoptosis. This oxidative stress further aggravated regenerative dysfunction as indicated by the decreased levels of Ki67, PCNA, Cyclin D1, and Cdk2. Conversely, these phenomena were attenuated by pretreatment with resveratrol. Moreover, resveratrol suppressed the elevation of p66shc in the liver by reversing Con-A-mediated downregulation of SIRT1. The findings suggest that resveratrol protected against Con A-induced hepatitis in aged mice by attenuating an aberration of immune response and liver regeneration, partially via the mechanism of SIRT1-mediated repression of p66shc expression.

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MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation

He,

Wang,

Liu

et al. 2023

Advanced Science

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Male‐specific lethal 1 (MSL1) is critical for the formation of MSL histone acetyltransferase complex which acetylates histone H4 Lys16 (H4K16ac) to activate gene expression. However, the role of MSL1 in liver regeneration is poorly understood. Here, this work identifies MSL1 as a key regulator of STAT3 and histone H4 (H4) in hepatocytes. MSL1 forms condensates with STAT3 or H4 through liquid–liquid phase separation to enrich acetyl‐coenzyme A (Ac‐CoA), and Ac‐CoA in turn enhances MSL1 condensate formation, synergetically promoting the acetylation of STAT3 K685 and H4K16, thus stimulating liver regeneration after partial hepatectomy (PH). Additionally, increasing Ac‐CoA level can enhance STAT3 and H4 acetylation, thus promoting liver regeneration in aged mice. The results demonstrate that MSL1 condensate‐mediated STAT3 and H4 acetylation play an important role in liver regeneration. Thus, promoting the phase separation of MSL1 and increasing Ac‐CoA level may be a novel therapeutic strategy for acute liver diseases and transplantation.

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Dysfunction of liver regeneration in aged liver after partial hepatectomy

Abstract: These results revealed that impaired liver regeneration was due to aging, which was expressed by decreased cell cycle and increased autophagy and apoptosis. Therefore, understanding the molecular basis for aged liver regeneration might provide a new therapeutic option for old patients.

Cited by 55 publications

References 38 publications

Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet

Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet

Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice

MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation

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