Department of Nutritional Sciences and Obesity Research Cluster, Texas Tech University, Lubbock, TX 79409, USA.
Department of Physiology, University of Peradeniya, 20400 Peradeniya, Sri Lanka.
Nutrients. 2019 Mar 12;11(3):599. doi: 10.3390/nu11030599.
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, concurrent with increased obesity. Thus, there is urgent need for research that can lead to effective NAFLD prevention/treatment strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA), improve inflammation- and dyslipidemia-related metabolic disorders; however, mechanisms mediating the benefits of n-3 PUFAs in NAFLD treatment are less understood. We previously reported that EPA reversed obesity-induced hepatic steatosis in high-fat (HF)-fed B6 mice. Utilizing a combination of biochemical analyses of liver tissues from HF and HF-EPA-fed mice and a series of in vitro studies in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells, we dissect the mechanistic effects of EPA in reducing hepatic steatosis, including the role of EPA-targeted microRNAs (miRNA). With EPA, hepatic lipid metabolism was improved in HF-EPA mice, as indicated by decreased protein and messenger RNA (mRNA) levels of fatty acid synthase (FASN) and acetyl-CoA carboxylase () gene, and increased mRNA levels for the peroxisome proliferator activated receptor-α (), and carnitine palmitoyltransferase () 1a and 2 genes in the HF-EPA mice. Additionally, inflammation was reduced, as shown by decreased tumor necrosis factor-alpha () gene expression. Accordingly, EPA also significantly reduced and mRNAs in human HepG2 cells. Glycolysis, estimated by extracellular acidification rate, was significantly reduced in HepG2 cells treated with EPA vs. vehicle. Furthermore, we identified several miRNAs that are regulated by EPA in mouse liver, including miR-19b-3p, miR-21a-5p, and others, which target lipid metabolism and inflammatory pathways. In conclusion, our findings provide novel mechanistic evidence for beneficial effects of EPA in NAFLD, through the identification of specific genes and miRNAs, which may be further exploited as future NAFLD therapies.
非酒精性脂肪性肝病（NAFLD）的患病率在全球范围内不断增加，同时肥胖症的发病率也在上升。因此，迫切需要开展能够制定出有效预防/治疗 NAFLD 策略的研究。ω-3 多不饱和脂肪酸（n-3 PUFA），包括二十碳五烯酸（EPA），可以改善与炎症和血脂异常相关的代谢紊乱；然而，n-3 PUFA 治疗 NAFLD 的作用机制还不太清楚。我们之前的研究报道，EPA 可以逆转高脂肪（HF）喂养的 B6 小鼠的肥胖诱导的肝脂肪变性。我们利用 HF 和 HF-EPA 喂养的小鼠的肝脏组织的生化分析以及肿瘤坏死因子-α（TNF-α）刺激的 HepG2 细胞的一系列体外研究的组合，剖析了 EPA 减轻肝脂肪变性的机制作用，包括 EPA 靶向 microRNAs（miRNA）的作用。在 HF-EPA 组中，EPA 改善了肝内脂质代谢，表现为脂肪酸合成酶（FASN）和乙酰辅酶 A 羧化酶（ACC）基因的蛋白和信使 RNA（mRNA）水平降低，过氧化物酶体增殖物激活受体-α（PPAR-α）和肉毒碱棕榈酰基转移酶（CPT）1a 和 2 基因的 mRNA 水平升高。此外，炎症反应降低，表现为肿瘤坏死因子-α（TNF-α）基因表达降低。相应地，EPA 还显著降低了人 HepG2 细胞中的 和 mRNA。用 EPA 处理 HepG2 细胞后，通过细胞外酸化率估计的糖酵解显著降低。此外，我们鉴定了几种在小鼠肝脏中受 EPA 调节的 miRNA，包括 miR-19b-3p、miR-21a-5p 等，这些 miRNA 靶向脂质代谢和炎症途径。总之，我们的研究结果为 EPA 在 NAFLD 中的有益作用提供了新的机制证据，通过鉴定特定的基因和 miRNA，可以进一步将其开发为未来的 NAFLD 治疗方法。
