Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and the cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically-modified mice and animal models. Lineage labelling using AAV-Tbg-Cre-treated Rosa26 mice or Sox9-Cre , Rosa26 mice was performed and Pxr-null mice or AAV Yap shRNA-treated mice were used to confirm the role of PXR or YAP. Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type and PXR-humanized mice but not in Pxr-null mice by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with yes-associated protein (YAP) and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. These findings revealed a novel function of PXR in enlarging liver size and changing liver cell fate via activation of the YAP signalling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate. This article is protected by copyright. All rights reserved.
Lipidomics, which reveals comprehensive characterization of molecular lipids, is a rapidly growing technology used in biomedical research. Lipid extraction is a critical step in lipidomic analysis. However, the effectiveness of different lipid extract solvent systems from cellular samples still remains unclear. In the current study, the protocol of reverse-phase liquid chromatography mass spectrometry (LC/MS)-based lipidomics was optimized for extraction and detection of lipids from human pancreatic cancer cell line PANC-1. Four different extraction methods were compared, including methanol/methyl-tert-butyl ether (MTBE)/HO, methanol/chloroform, methanol/MTBE/chloroform, and hexane/isopropanol. Data were acquired using high-resolution mass spectrometry in positive and negative ion modes respectively. The number of total detected and identified lipids was assessed with the aid of automated lipid identification software LipidSearch. Results demonstrated that methanol/MTBE/HO provided a better extraction efficiency for different lipid classes, which was chosen as the optimized extraction solvent system. This validated method enables highly sensitive and reproducible analysis for a variety of cellular lipids, which was further applied to an untargeted lipidomic study on human pancreatic cancer PANC-1 cell lines. Moreover, this optimized extraction solvent system can be further applied to other cancer cell lines with similar chemical and physical properties. Graphical abstract Optimized UHPLC-ESI-HRMS-based lipidomic analysis of cancer cells.
Background and Aims: Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. Approach and Results: In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Ppara fl/fl mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (Ppara ΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce
The carnitine palmitoyltransferase (CPT) family is essential for fatty acid oxidation. Recently, we found that CPT1C, one of the CPT1 isoforms, plays a vital role in cancer cellular senescence. However, it is unclear whether other isoforms (CPT1A, CPT1B, and CPT2) have the same effect on cellular senescence. This study illustrates the different effects of CPT knockdown on PANC-1 cell proliferation and senescence and MDA-MB-231 cell proliferation and senescence, as demonstrated by cell cycle kinetics, Bromodeoxyuridine incorporation, senescence-associated β-galactosidase activity, colony formation, and messenger RNA (mRNA) expression of key senescence-associated secretory phenotype factors. CPT1C exhibits the most substantial effect on cell senescence. Lipidomics analysis was performed to further reveal that the knockdown of CPTs changed the contents of lipids involved in mitochondrial function, and lipid accumulation was induced. Moreover, the different effects of the isoform deficiencies on mitochondrial function were measured and compared by the level of radical oxygen species, mitochondrial transmembrane potential, and the respiratory capacity, and the expression of the genes involved in mitochondrial function were determined at the mRNA level. In summary, CPT1C exerts the most significant effect on mitochondrial dysfunction-associated tumor cellular senescence among the members of the CPT family, which further supports the crucial role of CPT1C in cellular senescence and suggests that inhibition of CPT1C may represent as a new strategy for cancer treatment through the induction of tumor senescence.
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