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Pharmacologic Inhibition of Epidermal Growth Factor Receptor Suppresses Non-alcoholic Fatty Liver Disease in Murine Fast-food Diet Model

ABSTRACT: 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)

ORGANISM(S): Mus musculus

PROVIDER: GSE130528 | GEO | 2020/05/02

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:Fast food diet consumption and sedentary life style leads to energy excess, which elevates risks for obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and cancer. Exercise training conveys many health benefits in populations with or without these chronic conditions. Diet and exercise regulate gene expression by mediating epigenetic mechanisms globally and at select loci in an array of human tissues, however, such effects are less well documented in liver tissue. To dissect the epigenetic consequences of diet and exercise in liver, we measured DNA methylation using reduced representation bisulfite sequencing (RRBS) and transcriptome using RNA-seq in mice maintained on a fast food diet with sedentary lifestyle (FFC) or exercise (FFE) compared to control diet with (NCE) and without exercise (NCC). Our analyses demonstrate genome-wide differential DNA methylation at key regulatory regions, including different classes of promoters and enhancers, and differential regulation of gene clusters in each condition group. FFE gene expression is most differentially regulated, with enrichment of carbohydrate/lipid metabolic pathways and skeletal muscle development in altered gene sets. Through evaluation of putative protective effects of exercise on diet-induced DNA methylation and gene expression, we show that hypermethylation is effectively prevented, especially at promoters and enhancers, and hypomethylation is partially attenuated. We assessed diet-induced DNA methylation changes associated with cancer-related epigenetic modifications and identified significant increases at liver-specific enhancers in FFC and FFE, suggesting a repressive effect on the epigenomic signature specifying liver identity. Gaining methylation at a subset of gene promoters was associated with inhibition of tissue development and promotion of carcinogenic process. Taken together, our study demonstrates large-scale diet- and exercise-induced effects on the epigenetic landscape, emphasizing the functional relevance of epigenetic mechanisms as an interface between life-style modifications and phenotypic alterations.

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Pharmacologic Inhibition of Epidermal Growth Factor Receptor Suppresses Non-alcoholic Fatty Liver Disease in Murine Fast-food Diet Model

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