Phenobarbital, a hepatic metabolic enzyme inducer, inhibits preneoplastic hepatic lesions with expression of selective autophagy receptor p62 and ER-phagy receptor FAM134B in high-fat diet-fed rats through the inhibition of ER stress

Uomoto, Suzuka; Takesue, Keisuke; Shimuzu, Saori; Maeda, Natsuno; Ohshima, Kanami; Hara, Emika; Kobayashi, Mio; Takahashi, Yasunori; Shibutani, Makoto; Yoshida, Toshinori

doi:10.1016/j.fct.2023.113607

Cited by 4 publications

(6 citation statements)

References 52 publications

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“…In this study, a signi cant increase in Gpx2 gene expression in the BD + FL group suggested that FL induced an oxidative stress response; however, the effect remained limited, as other antioxidant genes were largely unaffected. Under our study conditions, we assessed mitophagy ux using immunohistochemistry-based clustering analysis involving mitophagy markers in background hepatocytes and preneoplastic lesions, following a previously reported methodology 34 to understand the role of mitophagy in FL and HFD-mediated hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate the relationship between LC3 and AMBRA1 expression, we compared the expression ratios of both indicators in background hepatocytes using cluster analysis, as previously reported 34 , aiming to elucidate the dynamics of autophagy ux (Supplemental Fig. 1).…”

Section: Cluster Analysis Of Lc3 Ambra1 and Parkin Expression In Back...mentioning

confidence: 99%

“…The number of Ki-67-positive cells per GST-P-positive focus was de ned as the labeling index (%) 31 . The GST-P-positive foci and the positivity rates for AMBRA1, LC3, and Parkin were collated for each individual and analyzed in groups, rather than individually, as previously reported 34 . For further analysis, the positive rates of LC3, AMBRA1, or Pink in GST-P-positive foci were plotted on the x-and y-axes, respectively.…”

Section: And Analysismentioning

confidence: 99%

“…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 .…”

Section: Introductionmentioning

confidence: 99%

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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

Preprint

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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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Section: Discussionmentioning

confidence: 99%

Section: Cluster Analysis Of Lc3 Ambra1 and Parkin Expression In Back...mentioning

confidence: 99%

Section: And Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Preprint

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“…FAM134B promotes the growth of liver cancer cells through its involvement in the endoplasmic reticulum stress pathway 24 . Endoplasmic reticulum stress plays an important role in liver growth and regenerative processes, particularly in the activation and proliferation of liver cancer cells 25 . Currently, research has revealed that endoplasmic reticulum stress may also inhibit cell autophagy, leading to metabolic disorders, apoptosis, and exacerbated inflammation 26 .…”

Section: Discussionmentioning

confidence: 99%

Upregulation of FAM134B inhibits endoplasmic reticulum stress‐related degradation protein expression and promotes hepatocellular carcinogenesis

Wang,

Liu,

Gong

et al. 2023

J Cellular Molecular Medi

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Endoplasmic reticulum (ER) stress can stimulate the proliferation and metastasis of hepatocellular carcinoma (HCC) cells while hindering apoptosis and immune system function, but the molecular mechanism of ER stress in HCC has yet to be fully studied. We aim to investigate the molecular mechanism by which FAM134B inhibits autophagy of HCC cells by reducing the expression of ER stress‐related degradation proteins. Clinical samples were collected for this study. Normal liver cell lines HL7702 and Hep3B and Huh7 HCC cell lines were cultured. Construction of FAM134B knockdown cell line. Cell proliferation was measured using the CCK‐8 assay, while cell migration and invasion capabilities were detected using the plate colony formation assay. Flow cytometry was used to detect the apoptosis rate. Transmission electron microscopy was used to observe the formation of autophagosomes. qRT‐PCR and WB detective expression changes related to autophagy proteins. Finally, the expression of the relevant proteins was observed by immunohistochemistry. The expression of FAM134B was significantly increased in human liver cancer tissue and HCC cell lines Hep3B and Huh7. After the lentiviral vector was transfected into Hep3B cells with sh‐FAM134B, results showed that sh‐FAM134B could effectively inhibit Hep3B cell proliferation and promote HCC cell apoptosis. Meanwhile, sh‐FAM134B could effectively induce the autophagy of Hep3B liver cancer cells. Immunohistochemistry results showed that sh‐FAM134B could effectively induce ER stress. FAM134B inhibits HCC cell autophagy and promotes the progression of liver cancer by inhibiting the expression of ER stress‐related degradation factors such as DERL2, EDEM1, SEL1L and HRD1.

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Mechanisms and therapeutic implications of selective autophagy in nonalcoholic fatty liver disease

Jin,

Li,

Xia

et al. 2024

Journal of Advanced Research

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Phenobarbital, a hepatic metabolic enzyme inducer, inhibits preneoplastic hepatic lesions with expression of selective autophagy receptor p62 and ER-phagy receptor FAM134B in high-fat diet-fed rats through the inhibition of ER stress

Cited by 4 publications

References 52 publications

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

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

Upregulation of FAM134B inhibits endoplasmic reticulum stress‐related degradation protein expression and promotes hepatocellular carcinogenesis

Mechanisms and therapeutic implications of selective autophagy in nonalcoholic fatty liver disease

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