Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
Laboratory of Biochemistry, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
Int J Mol Sci. 2020 Feb 11;21(4):1206. doi: 10.3390/ijms21041206.
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5' untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed.
非酒精性脂肪性肝病（NAFLD）是一种慢性疾病，其中肝细胞内的脂质以液滴形式过度积累。最近，越来越多的证据表明，持续的从头合成脂质可能在 NAFLD 中发挥重要作用。在与脂质积累相关的肝脏疾病中，已发现脂肪生成基因（包括 ATP-柠檬酸裂解酶（ACLY））的表达失调。ACLY 是一种普遍存在于细胞质中的酶，位于营养物质分解代谢和胆固醇及脂肪酸生物合成的交汇点。在本研究中，报道了脂肪变性细胞模型中 ACLY 表达的分子机制。我们在 ACLY mRNA 的 5'非翻译区鉴定到一个内部核糖体进入位点（IRES），该位点可以通过非依赖性帽机制支持有效的 mRNA 翻译。在脂肪变性的 HepG2 细胞中，ACLY 通过 IRES 介导的翻译而上调表达。由于已经证明细胞内的脂质积累会诱导内质网（ER）应激，因此还评估了该细胞途径在 ACLY 翻译调控中的参与情况。我们的结果表明，在 ER 应激的细胞中，通过 ACLY mRNA 的 IRES 介导翻译，ACLY 的表达增加。讨论了 ACLY 的无帽依赖翻译在 NAFLD 中的潜在作用。
