Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School of Nanjing University, Nanjing, China; Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Cell Mol Gastroenterol Hepatol. 2022;14(3):669-692. doi: 10.1016/j.jcmgh.2022.05.008. Epub 2022 May 26.
BACKGROUND & AIMS: Parenteral nutrition (PN) is a lifesaving therapy for patients with intestinal failure. Hepatic steatosis is a potentially fatal complication of long-term PN, but the involved pathological mechanisms are incompletely unclarified. Herein, we identify the role of protein phosphatase 2A (PP2A) in the pathogenesis of parenteral nutrition-associated hepatic steatosis (PNAHS).
Proteomic/phosphoproteomic analyses of liver samples from patients with PNAHS were applied to identify the mechanism of PNAHS. Total parenteral nutrition (TPN) mice model, in vivo, and in vitro experiments were used to assess the effect of PP2A-Cα on liver fatty acid metabolism.
Reduced expression of PP2A-Cα (catalytic subunit) enhanced activation of serine/threonine kinase Akt2 and decreased activation of adenosine monophosphate-activated protein kinase (AMPK) were associated with hepatic steatosis in patients with PNAHS. Mice given PN for 14 days developed hepatic steatosis, down-regulation of PP2A-Cα, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-Cα in mice given PN exacerbated Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation, whereas hepatocyte-specific PP2A-Cα overexpression significantly ameliorated hepatic steatosis accompanied with Akt2 suppression and AMPK activation. Additionally, pharmacological activation of Akt2 in mice overexpressing PP2A-Cα led to the aggravation of hepatic steatosis.
Our findings demonstrate that hepatic PP2A-Cα serves as a protective factor of PNAHS due to ameliorating hepatic steatosis and improving liver function. Our study provides a strong rationale that PP2A-Cα may be involved in the pathogenesis of PNAHS.
肠衰竭患者的救命疗法是肠外营养（PN）。长期 PN 会导致肝脂肪变性，这是一种潜在的致命并发症，但涉及的病理机制尚不完全清楚。在此，我们确定蛋白磷酸酶 2A（PP2A）在肠外营养相关肝脂肪变性（PNAHS）发病机制中的作用。
应用肝组织的蛋白质组学/磷酸化蛋白质组学分析鉴定 PNAHS 的发病机制。采用全胃肠外营养（TPN）小鼠模型，进行体内和体外实验，评估 PP2A-Cα 对肝脂肪酸代谢的影响。
PP2A-Cα（催化亚基）表达减少增强了丝氨酸/苏氨酸激酶 Akt2 的激活，降低了腺苷单磷酸激活蛋白激酶（AMPK）的激活，与 PNAHS 患者的肝脂肪变性有关。给予 PN 14 天的小鼠发生肝脂肪变性，PP2A-Cα 下调，Akt2 激活，AMPK 抑制。给予 PN 的 PP2A-Cα 肝细胞特异性缺失通过影响脂肪酸降解，加剧 Akt2 激活、AMPK 抑制和肝脂肪变性，而给予 PN 的 PP2A-Cα 肝细胞特异性过表达则显著改善肝脂肪变性，同时抑制 Akt2 激活和 AMPK 激活。此外，在过表达 PP2A-Cα 的小鼠中，药理学激活 Akt2 导致肝脂肪变性加重。
我们的研究结果表明，肝 PP2A-Cα 通过改善肝脂肪变性和肝功能，作为 PNAHS 的保护因素。我们的研究为 PP2A-Cα 可能参与 PNAHS 的发病机制提供了有力的依据。
