Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease, which progression is tightly regulated by transcription factors (TFs), nuclear receptors, and cellular enzymes. In this study, a label-free quantitative proteomic approach was used to determine the effect of the high-fat diet on the proteomics profile of liver tissue and to identify novel NAFLD related TFs. Mice were fed with HFD for 16 weeks to establish a NAFLD mouse model. Mice fed with normal chow diet were taken as controls. Liver samples were collected from each group for proteomics analysis. A total of 2298 proteins were quantified, among which 106 proteins were downregulated, while 256 proteins were upregulated in HFD-fed mice compared with the controls with fold change more than 1.5 and p value less than 0.05. Bioinformatic analysis revealed that metabolic-related functions and pathways were most significantly enriched. A subgroup of 11 TFs were observed to share interactions with metabolic-related enzymes and kinases by protein-protein interaction analysis. Among them, 7 TFs were selected for verification, and 3 TFs were finally validated, including Rbbp4, Tcea1, and ILF2. Downregulating each of the 3 TFs could significantly promote lipid accumulation in AML12 hepatocytes, by regulating the expression of fatty acid synthesis- or β-oxidation-related genes. In contrast, overexpression of Tcea1, Rbbp4, and ILF2, respectively, could ameliorate hepatocyte steatosis. These findings propose novel lipid metabolism related TFs, which might have potential roles in preventing NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is a predominant contributor to end-stage liver disease in the forthcoming decades. Polygonum perfoliatum L. (PPL) is an herbal medicine with anti-lipid peroxidation and anti-inflammatory properties. However, detailed hepatoprotective effects of PPL against NAFLD and its underlying mechanisms are not fully understood. Here, we found that PPL protects against high fat diet (HFD)-induced hepatic steatosis, lipid peroxidation, and glucose-lipid metabolism dysfunction in NAFLD mice. We therefore performed a label-free quantitative proteomic profiling analysis to determine the effect of PPL treatment on liver tissue proteomics and identified that activated PPARs/CPT1A/CPT2-mediated hepatic fatty acid β-oxidation (FAO) process was significantly altered. In vitro treatment of hepatocytes with PPL confirmed this altered process and FAO inhibitor etomoxir (ETO) attenuated the lipid-lowering activity of PPL in hepatocytes. Ultra-high-performance liquid chromatography/Q Exactive-HFX (UPLC/QE-HFX) was used to determine the material basis of anti-NAFLD activity of PPL. Our results have demonstrated the efficacy and potential mechanisms of PPL as an effective pharmacological therapy of NAFLD.
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