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Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis

ABSTRACT: Herein we identified Niemann–Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. Knockout of PKM2 enhanced NPC1L1 expression in breast cancer cells, while reducing the peroxisome proliferator-activated receptor α (PPARα) signaling pathway. Fenofibrate, a PPARα agonist, promoted NPC1L1 expression. Combined administration of fenofibrate and ezetimibe, a NPC1L1 inhibitor, significantly induced cytoplasmic vacuolation and cell apoptosis. Mechanistically, combined administration activated the inositol required enzyme 1α(IRE1α)- x box binding protein spliced (XBP1s) and lysine demethylase 6B (KDM6B). XBP1s interacted with KDM6B to activate genes involved in unfold protein response through demethylating di- and tri-methylated lysine 27 of histone H3 (H3K27) and consequentially increasing the level of H3K27 acetylation in breast cancer cell lines. Fenofibrate and ezetimibe synergistically inhibited tumor growth and lung metastasis in vivo. Together, our findings reveal that dual targeting PPARα and NPC1L1 may be developed as a new regimen for breast cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285705 | GEO | 2025/02/24

REPOSITORIES: GEO

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Project description:The role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the effect of PPARα activation in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver by combining transcriptomics with the use of hepatocyte humanized livers. To that end, chimeric mice containing hepatocyte humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days. Livers were collected and analysed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on fenofibrate treatment in normal mice. The human hepatocytes exhibited excessive lipid accumulation. Fenofibrate increased the size of the mouse but not human hepatocytes, and tended to reduce steatosis in the human hepatocytes. Quantitative PCR indicated that induction of PPARα targets by fenofibrate was less pronounced in the human hepatocytes than in the residual mouse hepatocytes. Transcriptomics analysis indicated that, after filtering, a total of 282 genes was significantly different between fenofibrate- and control-treated mice (P<0.01). 123 genes were significantly lower and 159 genes significantly higher in the fenofibrate-treated mice, including many established PPARα targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2. According to gene set enrichment analysis, fenofibrate upregulated interferon/cytokine signaling-related pathways in hepatocyte humanized liver, but downregulated these pathways in normal mouse liver. Also, fenofibrate downregulated pathways related to DNA synthesis in hepatocyte humanized liver but not in normal mouse liver. The results support the major role of PPARα in regulating hepatic lipid metabolism, and underscore the more modest effect of PPARα activation on gene regulation in human liver compared to mouse liver. The data suggest that PPARα may have a suppressive effect on DNA synthesis in human liver, and a stimulatory effect on interferon/cytokine signalling.

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Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis

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