Polyene Phosphatidylcholine Ameliorates High Fat Diet-Induced Non-alcoholic Fatty Liver Disease via Remodeling Metabolism and Inflammation.

Yang Lu,Menglu Zhou,Jinxiu Zhao,Jiacheng Wu,Fenfen Sun,Wei Pan,Qisi Lin,Pengfei Jiang,Daxiang Xu,Tingting Feng,Xiaoying Yang,Mengyu Dai

doi:10.3389/fphys.2022.810143

Abstract

Recent years have witnessed a rise in the morbidity of non-alcoholic fatty liver disease (NAFLD), in line with the global outbreak of obesity. However, effective intervention strategy against NAFLD is still unavailable. The present study sought to investigate the effect and mechanism of polyene phosphatidylcholine (PPC), a classic hepatoprotective drug, on NAFLD induced by high fat diet (HFD). We found that PPC intervention reduced the mass of liver, subcutaneous, epididymal, and brown fats in HFD mice. Furthermore, PPC supplementation significantly mitigated liver steatosis and improved glucose tolerance and insulin sensitivity in HFD mice, which was accompanied by declined levels of hepatic triglyceride, serum triglyceride, low density lipoprotein, aspartate aminotransferase, and alanine aminotransferase. Using transcriptome analysis, there were 1,789 differentially expressed genes (| fold change | ≥ 2, P < 0.05) including 893 upregulated genes and 896 downregulated genes in the HFD group compared to LC group. A total of 1,114 upregulated genes and 1,337 downregulated genes in HFD + PPC group were identified in comparison to HFD group. With the help of Gene Ontology (GO) analysis, these differentially expressed genes between HFD+PPC and HFD group were discovered related to “lipid metabolic process (GO: 0006629),” “lipid modification (GO: 0030258),” and “lipid homeostasis (GO: 0055088)”. Though Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found pathways associated with hepatic homeostasis of metabolism and inflammation. Notably, the pathway “Non-alcoholic fatty liver disease (mmu04932)” (P-value = 0.00698) was authenticated in the study, which may inspire the potential mechanism of PPC to ameliorate NAFLD. The study also found that lipolysis, fatty acid oxidation, and lipid export associated genes were upregulated, while the genes in uptake of lipids and cholesterol synthesis were downregulated in the liver of HFD mice after PPC supplementation. Interestingly, PPC attenuated the metabolic inflammation via inhibiting pro-inflammatory macrophage in the livers of mice fed by HFD. In summary, this study demonstrates that PPC can ameliorate HFD-induced liver steatosis via reprogramming metabolic and inflammatory processes, which inspire clues for further clarifying the intervention mechanism of PPC against NAFLD.

Highlights

Abnormal lipid deposition in the liver leads to non-alcoholic fatty liver disease (NAFLD), which encompasses a spectrum of liver disorders ranging from hepatic steatosis to non-alcoholic steatohepatitis and may lead to cirrhosis (Manne et al, 2018)
This study firstly evaluated the effect of PPC supplementation on high fat diet (HFD)-induced metabolic disorder
PPC treatment inhibited the upregulated expression of these proinflammatory cytokines (Figure 8F). Those alternations occurred in the epididymal fat in the HFD mice after PPC treatment (Supplementary Figure 4). These results showed that PPC supplementation enhances lipolysis and alleviates inflammation in the fat tissues of mice fed by HFD

Summary

Introduction

Abnormal lipid deposition in the liver leads to non-alcoholic fatty liver disease (NAFLD), which encompasses a spectrum of liver disorders ranging from hepatic steatosis to non-alcoholic steatohepatitis and may lead to cirrhosis (Manne et al, 2018). As the most common chronic liver disease worldwide, NAFLD affects 25% of the global adult population (Younossi et al, 2019) and its prevalence is expected to increase rapidly soon owing to the global epidemics of obesity and type 2 diabetes (Park et al, 2020). It is increasingly clear that NAFLD affects the liver but can increase the risk of developing extrahepatic diseases, including metabolic syndrome (Dietrich and Hellerbrand, 2014; Yki-Järvinen, 2014), cardiovascular disease (Kim et al, 2012), and chronic kidney disease (Musso et al, 2015), placing a heavy burden on health-care resources. The effective intervention strategy against NAFLD is still unavailable. The rebuilding of hepatic lipid metabolism homeostasis can effectively prevent NAFLD (Seebacher et al, 2020). Taken together, reprogramming hepatic metabolism and inflammation provides an attractive strategy for NAFLD intervention

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Results

Conclusion