Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
School of Pharmacy, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China.
Biochim Biophys Acta Mol Basis Dis. 2020 Oct 1;1866(10):165854. doi: 10.1016/j.bbadis.2020.165854. Epub 2020 Jun 2.
Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic steatosis, inflammation and liver fibrosis and has become one of the leading causes of hepatocellular carcinoma and liver failure. However, the underlying molecular mechanism of hepatic steatosis and the progression to nonalcoholic steatohepatitis (NASH) are not fully understood. Herein, we discovered that AMPKα2 catalytic subunit showed reduced expression in the liver following high fat diet (HFD) feeding to mice. Importantly, knockout of AMPKα2 in mice aggravated NAFLD, hepatic steatosis, inflammation and fibrosis. On the other hand, hepatocyte-targeted overexpression of AMPKα2 prevented or reversed NAFLD indications. In vivo mechanistic studies revealed that increased phosphorylation of IKKα/β and NF-κB in HFD-fed AMPKα2 mice compared to WT mice, and treatment of these mouse cohorts with an inhibitor of NF-κB signaling for 4 weeks, effectively attenuated the progression of steatohepatitis and metabolic disorder features. In summary, AMPKα2 provides a protective role in the process of hepatic steatosis to NASH progression through suppression of liver NF-κB signaling.
非酒精性脂肪性肝病（NAFLD）与肝脂肪变性、炎症和肝纤维化有关，已成为肝细胞癌和肝衰竭的主要原因之一。然而，肝脂肪变性的潜在分子机制以及向非酒精性脂肪性肝炎（NASH）的进展尚不完全清楚。在此，我们发现高脂肪饮食（HFD）喂养的小鼠肝脏中 AMPKα2 催化亚基的表达减少。重要的是，在小鼠中敲除 AMPKα2 会加重 NAFLD、肝脂肪变性、炎症和纤维化。另一方面，肝实质细胞靶向过表达 AMPKα2 可预防或逆转 NAFLD 指标。体内机制研究表明，与 WT 小鼠相比，HFD 喂养的 AMPKα2 小鼠中 IKKα/β 和 NF-κB 的磷酸化增加，用 NF-κB 信号抑制剂治疗这些小鼠 4 周，可有效减轻脂肪性肝炎和代谢紊乱特征的进展。总之，AMPKα2 通过抑制肝脏 NF-κB 信号在肝脂肪变性向 NASH 进展过程中发挥保护作用。
