Hepatic lipotoxicity, hepatocyte dysfunction/cell death induced by saturated fatty acids (SFA), plays a central role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanisms remain unclear. Palmitate is the most abundant SFA in the circulation. In this study, via a small-scale screening of chemical inhibitors using AML12 hepatocytes, we identified mTOR complex 1 (mTORC1) to be a culprit in palmitate-induced cell death in hepatocytes in that mTOR inhibition is protective against palmitate-induced cell death. The protective effects of mTORC1 inhibition are independent of autophagy induction as autophagy inhibition failed to ablate the mTORC1 inhibitor-conferred protection. We have previously reported that the endonuclease activity of inositol-requiring enzyme 1a (IRE1a), one of three canonical signaling pathways of endoplasmic reticulum (ER) stress, was implicated in palmitate-induced cell death in hepatocytes. The continuous mechanistic investigation in this study revealed that IRE1α is a downstream target of mTORC1 activation upon palmitate exposure and the inhibition of either its endonuclease activity or kinase activity protected against the lipotoxic effect of palmitate. Our research further uncovered that protein palmitoylation is potentially involved in palmitate-induced mTORC1 activation and lipotoxicity in hepatocytes. 2-bromopalmitate, a protein palmitoylation inhibitor, ameliorated palmitate-triggered mTORC1 activation, concomitant with prevention of lipotoxicity in hepatocytes. Collectively, our data have identified that mTORC1 and ER stress are coordinately implicated in hepatocyte cell death in response to palmitate exposure and suggests that this pathway may potentially serve as a therapeutic target for the treatment of NAFLD as well as other metabolic disorders involving lipotoxicity.

中文翻译：

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肌醇需要酶 1 α (IRE1a) 将棕榈酸诱导的 mTOR 激活和肝细胞中的脂毒性联系起来


饱和脂肪酸 (SFA) 诱导的肝脂毒性、肝细胞功能障碍/细胞死亡在非酒精性脂肪肝 (NAFLD) 的发病机制中发挥着核心作用；然而，其根本机制仍不清楚。棕榈酸酯是流通中最丰富的 SFA。在这项研究中，通过使用 AML12 肝细胞对化学抑制剂进行小规模筛选，我们发现 mTOR 复合物 1 (mTORC1) 是棕榈酸酯诱导的肝细胞细胞死亡的罪魁祸首，因为 mTOR 抑制可以防止棕榈酸酯诱导的细胞死亡。 mTORC1 抑制的保护作用与自噬诱导无关，因为自噬抑制未能消除 mTORC1 抑制剂赋予的保护。我们之前曾报道，肌醇需求酶 1a (IRE1a) 是内质网 (ER) 应激的三个经典信号通路之一，其核酸内切酶活性与棕榈酸诱导的肝细胞细胞死亡有关。本研究中的连续机制研究表明，IRE1α 是棕榈酸酯暴露后 mTORC1 激活的下游靶标，并且其核酸内切酶活性或激酶活性的抑制可防止棕榈酸酯的脂毒性作用。我们的研究进一步发现，蛋白质棕榈酰化可能参与棕榈酸酯诱导的 mTORC1 激活和肝细胞脂毒性。 2-溴棕榈酸酯是一种蛋白质棕榈酰化抑制剂，可改善棕榈酸酯触发的 mTORC1 激活，同时预防肝细胞的脂毒性。 总的来说，我们的数据发现，mTORC1 和 ER 应激协同参与棕榈酸盐暴露引起的肝细胞死亡，并表明该途径可能作为治疗 NAFLD 以及涉及脂毒性的其他代谢性疾病的治疗靶点。