Hepatic polyploidization is closely linked to the progression of nonalcoholic fatty liver disease (NAFLD); however, the underlying molecular mechanism is not clearly understood. In this study, we demonstrated the role of RORα in the maintenance of genomic integrity, particularly in the pathogenesis of NAFLD, using the high-fat diet (HFD)-fed liver-specific RORα knockout (RORα-LKO) mouse model. First, we observed that the loss of hepatic retinoic acid receptor-related orphan receptor α (RORα) accelerated hepatocyte nuclear polyploidization after HFD feeding. In 70% partial hepatectomy experiments, enrichment of hepatocyte polyploidy was more obvious in the RORα-LKO animals, which was accompanied by early progression to the S phase and blockade of the G2/M transition, suggesting a potential role of RORα in suppressing hepatocyte polyploidization in the regenerating liver. An analysis of a publicly available RNA-seq and chromatin immunoprecipitation-seq dataset, together with the Search Tool of the Retrieval of Interacting Genes/Proteins database resource, revealed that DNA endoreplication was the top enriched biological process gene ontology term. Furthermore, we found that E2f7 and E2f8, which encode key transcription factors for DNA endoreplication, were the downstream targets of RORα-induced transcriptional repression. Finally, we showed that the administration of JC1-40, an RORα activator (5 mg/kg body weight), significantly reduced hepatic nuclear polyploidization in the HFD-fed mice. Together, our observations suggest that the RORα-induced suppression of hepatic polyploidization may provide new insights into the pathological polyploidy of NAFLD and may contribute to the development of therapeutic strategies for the treatment of NAFLD.
The common and important change of pulmonary hemodynamics is represented by increased or decreased pulmonary blood flow (PBF) and increased pulmonary vascular resistance (PVR). We made 3 hemodynamic models in 5 dogs, that is, increased and decreased PBF model and increased PVR model. CT perfusion scan was performed.Perfusion parameters including blood flow (BF), blood volume (BV), mean transit time (MTT), and maximal slope (MS) were analyzed. In normal state, blood flow was affected by gravity and dependent area showed higher BF, BV and lower MS, MTT than non-dependent area. First, decreased PBF model showed no significant change in BV and elongation of MTT. Secondly, increased PBF model showed slightly increased BV and decreased MTT. Thirdly, increased PVR model showed significant decrease of BF, BV, and MS and slight increase of MTT without statistical significance. However, it was noticeable that the distribution of MTT according to gravity in normal lung was completely reversed in increased PVR model. In conclusion, on the basis of our understanding of perfusion characteristic in normal state, we can detect and evaluate the abnormal regional hemodynamic change in lung.Predicting the change of pulmonary vascular resistance should be possible by thorough analysis of CT perfusion parameters.
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