Inhibition of autophagy with expression of NADPH oxidase subunit p22phox in preneoplastic lesions in a high-fat diet and streptozotocin-related hepatocarcinogenesis rat model

Ichikawa, Ryo; Nakahara, Jin; Kobayashi, Mio; Yamashita, Risako; Uomoto, Suzuka; Ohshima, Kanami; Hara, Erika; Ito, Yuko; Shibutani, Makoto; Yoshida, Toshinori

doi:10.2131/jts.47.289

Cited by 1 publication

(1 citation statement)

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“…This model, based on the medium-term hepatocarcinogenesis assay 32 , served as a valuable tool for understanding the augmentation of autophagy in precancerous lesions facilitated by fatty liver conditions [28][29][30][31] . This model is particularly advantageous since hepatic precancerous lesions speci cally express the autophagosome marker LC3 and the cargo receptor p62 29,31,33 . Using immunohistochemical techniques and cluster analysis using autophagy markers, we investigated the role of autophagy in small precancerous lesions in rat livers 34 .…”

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confidence: 99%

Flutamide exacerbates steatosis and promotes early hepatocarcinogenesis in high-fat diet-fed non-obese steatotic rats: Insights from clustering analysis of mitophagy regulators AMBRA1 and LC3

Hara,

Ohshima,

Zeng

et al. 2024

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Flutamide (FL), a non-steroidal drug used for its anti-androgenic, anticancer,and disrupting endocrine properties, induces mitochondrial toxicity and drug metabolism enzymesand promotes hepatocarcinogenesis. The inhibition of mitophagy, leading to the accumulation of damaged mitochondria, is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of FL in high-fat diet (HFD)-induced non-obese steatosis rats, categorized into four groups: basal diet (BD), BD + FL, HFD, and HFD + FL. The introduction of FL exacerbated HFD-induced steatosis and marginally increased preneoplastic lesions. To analyzehepatic preneoplastic lesions, we divided them into clusters based on the expression ratios of the mitophagy regulators LC3 and AMBRA1. The expression rates of LC3 and AMBRA1 in these precancerous lesions were classified into three clusters using k-means clustering. The HFD group exhibited an increased ratio of mitophagy inhibition clusters, as indicated by decreased LC3 and increased AMBRA1 levels in background hepatocytes and preneoplastic lesions. FL counteracted HFD-mediated mitophagy inhibition, as indicated by increased LC3 and decreased AMBRA1 levels in background hepatocytes. Our clustering analysis revealed that FL-induced mitophagy induction relied on Parkin expression. The present study underscores the significance of cluster analysis in understanding the role of mitophagy within small preneoplastic lesions and suggests that FL may potentially exacerbate NAFLD-associated hepatocarcinogenesis by affecting mitophagy.

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