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Inhibition of phospholipase D1 ameliorates NAFLD by reducing PPARγ/CD36 pathway mediated lipid accumulation in hepatocytes

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE207281 | GEO | 2023/08/01

REPOSITORIES: GEO

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Project description:EGFR is a critical regulator of hepatocyte proliferation and liver regeneration. Our recent work indicated EGFR can also regulate lipid metabolism during liver regeneration after partial-hepatectomy. Based on these findings, we investigated role of EGFR in a mouse model of NAFLD utilizing a pharmacological inhibition strategy. C57BL6/J mice were fed chow-diet, or fast-food diet with/without EGFR inhibitor (Canertinib) for 2-months. EGFR inhibition completely prevented development of steatosis and liver injury in this model. In order to study if EGFR inhibition can reverse NAFLD progression, mice were fed fast-food diet for 5-months, with/without Canertinib-treatment for the last 5-weeks of the study. EGFR-inhibition remarkably decreased steatosis, liver injury, fibrosis and improved glucose tolerance. Microarray analysis revealed ~40% of genes altered by fast-food diet were differentially expressed after EGFR-inhibition, and thus, are potentially regulated by EGFR. Several genes and enzymes related to lipid metabolism (particularly fatty-acid synthesis and lipolysis), which were disrupted by fast-food diet, were found to be modulated by EGFR. Several crucial transcription factors that play a central role in regulating these lipid metabolism genes during NAFLD, including PPARγ, SREBF1, ChREBP and HNF4α, were also found to be modulated by EGFR. In fact, ChIP-analysis revealed PPARγ binding to several crucial lipid metabolisms genes (Fasn, Scd1 and Plin2) was drastically reduced by EGFR inhibition. Further upstream, EGFR-inhibition suppressed AKT signaling, which is known to control these transcription factors, including PPARγ and SREBF1, in NAFLD models. Lastly, the effect of EGFR in FFD-induced fatty-liver phenotype was not shared by receptor-tyrosine-kinase MET, as investigated using MET-KO mice. In-conclusion, our study revealed a role of EGFR in NAFLD and the potential of EGFR-inhibition as a treatment strategy for NAFLD. We used microarrays to detail the global programme of gene expression in liver of C57BL6/J mice fed fast-food diet mice treated with EGFR inhibitor (canertinib)

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Inhibition of phospholipase D1 ameliorates NAFLD by reducing PPARγ/CD36 pathway mediated lipid accumulation in hepatocytes

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