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Transcriptome changes in C57BL/6 mice after a high-fat diet

ABSTRACT: Background and aims: Trichosanthis Pericarpium injection (TPI) produces a significant effect on regulating lipid metabolism and antioxidation, whose effects on non-alcoholic fatty liver disease (NAFLD) still remain unclear. In this study, we delved into the pharmacological functions of TPI on NAFLD and its underlying mechanisms. Methods: NAFLD mice model was induced by administering a high-fat diet (HFD) for 12 weeks, followed by intraperitoneal injection of TPI for 4 weeks. Concurrently, to explore the potential mechanisms, we utilized AML12 cells exposed to oleic acid (OA) as an in vitro model. Non target metabolomics and transcriptomics were used to explore the mechanism by which TPI improves lipid metabolism in mouse liver. Results: Our findings indicate that TPI significantly improved metabolic abnormalities and hepatic fat deposition in HFD mice. TPI treatment also yielded analogous results in AML12 cells treated with OA. Metabolomic analysis revealed alterations in metabolites in NAFLD mice, with ABC transporters exhibiting the most prominent changes. Further screening of gene changes related to this pathway showed a significant increase in ABCC5 expression in the NAFLD mice, while TPI treatment effectively reduced the expression level of ABCC5. Transcriptomic analysis demonstrated a marked increase in the expression of the transcription factor KLF6 in the NAFLD group, which positively correlated with ABCC5 expression. Further luciferase reporter gene experiments confirmed that KLF6 can directly regulate the expression of ABCC5, thereby affecting lipid metabolism and participating in the development of NAFLD. Notably, TPI treatment was able to reverse this process. Conclusions: In conclusion, TPI improves NAFLD by alleviating hepatic lipid metabolism dysregulation through the KLF6/ABCC5 pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE273292 | GEO | 2024/07/29

REPOSITORIES: GEO

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Project description:Objective：Phospholipase D1 (PLD1), a phosphatidylcholine-hydrolyzing enzyme, has been found to be involved in cellular lipid metabolism. However, how PLD1 involves in hepatocyte lipid metabolism and thus affects non-alcoholic fatty liver diseases (NAFLD) has not been explicitly explored. Method: NAFLD is induced in hepatocyte-specific Pld1 knockout (Pld1(H)-KO) mice or control (Pld1-Flox) mice with a high fat diet (HFD) for 20 weeks. Plasma glucose and lipid levels, liver lipid and function parameters and inflammation- and fibrogenesis-related gene expression levels were studied. Changes in lipid composition of liver were detected by lipidomic analyses. Changes in gene expression profile were detected by mRNA sequencing. In vitro, alpha mouse liver 12 (AML12) cells were incubated with sodium palmitate (SP) to explore the mechanisms of PLD1 on development of NAFLD. The protein levels of PLD1 and CD36 were detected in the liver tissues of NAFLD patients. Finally, the therapeutic effect of NAFLD by inhibiting PLD with 5-Fluoro-2-indolyl deschlorohalopemide (FIPI) was examined. Results: PLD1 expression levels were increased in the liver tissues of NAFLD patients and the hepatocytes of HFD-induced mice. Compared with Pld1-Flox mice, Pld1(H)-KO mice exhibited lower plasma glucose and lipids levels, and decreased lipid accumulation, inflammation and fibrosis related gene expression levels in the liver tissues after HFD feeding. Inhibition of hepatocyte PLD1 significantly altered lipid composition, especially phosphatidic acids (PA) and lyso-PAs (LPA) levels in the liver tissues after NAFLD. Transcriptomic analysis showed that hepatocyte specific deficiency of PLD1 mainly decreased CD36 expression levels in the NAFLD liver tissues, which was confirmed at the protein and gene expression levels. In vitro, inhibition of PLD1 markedly decreased CD36 expression and lipid accumulation in SP treated AML12 cells. Furthermore, PA, the downstream product catalyzed by PLD1, increased the expression levels of CD36 and lipid accumulation in vitro, which was reversed by PPARγ antagonist. These suggested that PPARγ played an important role in transcriptional regulation of CD36 expression after PA stimulation. Finally, PLD inhibitor FIPI had significant therapeutic effect on HFD-induced NAFLD. Conclusion: Hepatocyte-specific deficiency of PLD1 ameliorates lipid accumulation and NAFLD development by inhibiting PPARγ/CD36 pathway conducted by PA.

Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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Transcriptome changes in C57BL/6 mice after a high-fat diet

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