Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis

Kurosaki, Shigeyuki; Nakagawa, Hayato; Hayata, Yuki; Kawamura, Satoshi; Yamada, Toshimoto; Uchino, Katsuyoshi; Hayakawa, Yoku; Suzuki, Nobumi; Hata, Mitsumasa; Tsuboi, Masamichi; Kinoshita, Hiroto; Tanaka, Yasuo; Nakatsuka, Takuma; Hirata, Yoshihiro; Tateishi, Keisuke; Koike, Kazuhiko

doi:10.1016/j.jhepr.2021.100315

Cited by 17 publications

(14 citation statements)

References 40 publications

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“…Furthermore, we analyzed cell death by TUNEL staining. As reported previously ( 26 ), apoptotic cells and necrotic cells were stained as nuclear fragmentation and diffuse cytoplasmic patterns, respectively, in the CDAHFD model. TUNEL + dying cells were more frequently observed in SCAP ΔL mice compared with Scap fl/fl mice ( Supplemental Figure 5E ).…”

Section: Resultssupporting

confidence: 80%

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Kawamura¹,

Kurosaki²,

Tange³

et al. 2022

Journal of Clinical Investigation

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Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

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Section: Resultssupporting

confidence: 80%

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Kawamura¹,

Kurosaki²,

Tange³

et al. 2022

Journal of Clinical Investigation

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“…In contrast, pericentral zone 3 hepatocytes express a wide range of cytochrome P450 and other detoxification enzymes, which enable them to efficiently metabolize toxic substances and endogenous metabolites. 4 Nonparenchymal cells such as liver sinus ECs (LSECs), hepatic stellate cells (HSCs), and immune cells also exhibit zonated functions. 1,5 The concept of functional zonation can be used to explain zonated liver injury.…”

Section: Lay Summarymentioning

confidence: 99%

Emerging Roles of Spatial Transcriptomics in Liver Research

Fujiwara,

Kimura,

Nakagawa

2024

Semin Liver Dis

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The application of spatial transcriptomic technologies has significantly expanded our biological understanding. Hepatic intricate cellular heterogeneity and the pivotal role of zonation in maintaining hepatic function underscore how these technologies can unravel the complex spatial and cellular dynamics within both healthy and diseased livers. The article provides a comprehensive overview of the technical innovations and bioinformatics strategies that underpin spatial transcriptome analysis. Further, through recent discoveries in liver biology and pathology, enabled by these advanced methodologies, the review illustrates novel cell types, cell-cell interactions, and cellular reprograms in healthy and injured livers, as well as tumor microenvironment associated with patient prognosis and response to immune checkpoint inhibitors. With emphasizing the challenges and future directions, it points to the immense promise these technologies hold for identifying new therapeutic targets and advancing personalized medicine in hepatology, despite the hurdles in widespread adoption and standardization.

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“…Hepatocytes that receive Wnt/β‐catenin signaling from the microenvironment have high tumor potential, and the activation of this signaling pathway plays an important role throughout liver regeneration and hepatocarcinogenesis during chronic liver injury 136,137 . Wnt/β‐catenin signaling pathway can also affect HCC through different impacts on TAMs.…”

Section: Signaling Pathway/axis Involved In Hcc Via Tamsmentioning

confidence: 99%

The role of tumor‐associated macrophages in hepatocellular carcinoma progression: A narrative review

Zhang,

Yu,

Zhao

et al. 2023

Cancer Medicine

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, with complex etiology and mechanism, and a high mortality rate. Tumor‐associated macrophages (TAMs) are an important part of the HCC tumor microenvironment. Studies in recent years have shown that TAMs are involved in multiple stages of HCC and are related to treatment and prognosis in HCC. The specific mechanisms between TAMs and HCC are gradually being revealed. This paper reviews recent advances in the mechanisms associated with TAMs in HCC, concentrating on an overview of effects of TAMs on drug resistance in HCC and the signaling pathways linked with HCC, providing clues for the treatment and prognosis determination of HCC.

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Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis

Cited by 17 publications

References 40 publications

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Emerging Roles of Spatial Transcriptomics in Liver Research

The role of tumor‐associated macrophages in hepatocellular carcinoma progression: A narrative review

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