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Rab7 Deletion Drives Hepatocyte Apoptosis and Fibrogenesis in the Liver

ABSTRACT: BACKGROUND AND AIMS: Liver fibrosis (LF) is kept in check by regulatory machinery that switches off signaling pathways responsible for cell death and subsequent scar tissue formation. Hepatocyte injury is essential for the initiation and development of LF, yet the underlying mechanism remains elusive. The endosome-lysosome system is vital for cell survival, and the small GTPase RAB7 regulates several functions of this system. Herein, we explored the role of RAB7 in hepatocyte function and homeostasis. APPROACH AND RESULTS: The expression level of Rab7 was assessed in the liver sections of the mouse LF model and of in patients with LF. Hepatocyte-specific Rab7 knockout mice were generated by crossing Rab7-floxed mice with mice expressing albumin Cre recombinase. Hepatocellular Rab7 deficiency induced spontaneous liver fibrosis as early as 9 weeks of age, and increased sensitivity to liver damage following CCL4 injury. Integrative analyses of transcriptome and targeted lipids omics profiling was performed to explore downstream mechanisms. RAB7 deficiency induced ceramide accumulation, which resulted in hepatocyte apoptosis, thereby promoting HSCs activation. Mechanistically, RAB7 regulates Sphingomyelin Phosphodiesterase 3 (SMPD3), an enzyme of the sphingomyelinase pathway for ceramide synthesis, in a Farnesoid X receptor (FXR) dependent manner. Strikingly, a pharmacological inhibitor of SMPD3, GW4869 impeded spontaneous LF due to hepatocyte-Rab7 deficiency and alleviated LF in mice with CCL4 injury. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that Rab7 deficiency leads to hepatocyte apoptosis and fibrogenesis in the liver, indicating that targeting the RAB7/FXR/SMPD3 axis holds promising therapeutic potential for LF. Keywords: liver fibrosis; hepatocyte; Ras-related protein Rab-7a; Sphingomyelin Phosphodiesterase 3; ceramide

ORGANISM(S): Mus musculus

PROVIDER: GSE280561 | GEO | 2026/10/01

REPOSITORIES: GEO

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			Action	DRS
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	GSE280561_gene.count.anno.xls.gz	Xls
	GSE280561_gene.fpkm.anno.xls.gz	Xls

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Project description:We have used human umbilical vein endothelial cell line (HUVEC) as a model to investigate the effect of ultrasound (US) activated micro-bubbles on sensitizing the tumour response to radiation and to check the implication of this approach on gene expression. The use of micro-bubbles in cancer therapy is a novel approach that is being recently investigated, and patterns of gene expressions were not yet characterized. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach.

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Rab7 Deletion Drives Hepatocyte Apoptosis and Fibrogenesis in the Liver

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