Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Free Radic Biol Med. 2021 Feb 1;163:220-233. doi: 10.1016/j.freeradbiomed.2020.12.011. Epub 2020 Dec 25.
Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent liver disease linked to obesity and associated complications. Endoplasmic reticulum (ER) stress provokes dysfunction in lipid metabolism, which often leads to a progression of obesity-induced hepatic steatosis to NASH. However, the underlying mechanisms in which ER stress in adipose tissue induces hepatic pathology remain elusive. Here, we used male C57BL/6J mice to develop an animal model of NASH induced by a high fat (HFD) diet and methionine- and choline-deficient (MCD) diets. Using a gene-silencing approach with a recombinant lentiviral vector and extensive LC-MS/MS-based proteomics and lipidomics, we demonstrate that the ER stress-induced adipocyte-secreted exosome (ATEx) orchestrates lipid dynamics in the liver. We also noted that ATEx causes hepatic steatosis, inflammation, and fibrosis that lead to NASH through initial accumulation of glycerol and triglycerides in hepatocytes. We also determined that aldo-keto-reductase 1B7 (Akr1b7), a key mediator in liver lipid metabolism, is involved in ATEx-mediated NASH induction. Of note, Akr1b7 deficiency in ER stress-induced ATEx strongly protected the murine liver against HFD and MCD-induced NASH. Our results indicated that ER stress-induced, adipocyte-secreted ATEx triggers NASH by delivering exosomal AKR1B7 to, and elevating glycerol level, in hepatocytes. These findings suggest potential therapeutic strategie that target ATEx to prevent or manage obesity-induced NASH.
非酒精性脂肪性肝炎（NASH）是一种与肥胖相关的日益普遍的肝脏疾病，其与肥胖相关并发症有关。内质网（ER）应激会引发脂质代谢功能障碍，这通常会导致肥胖引起的肝脂肪变性向 NASH 进展。然而，脂肪组织中 ER 应激如何诱导肝病理的潜在机制仍不清楚。在这里，我们使用雄性 C57BL/6J 小鼠建立了高脂肪（HFD）饮食和蛋氨酸和胆碱缺乏（MCD）饮食诱导的 NASH 动物模型。我们使用重组慢病毒载体的基因沉默方法以及广泛的 LC-MS/MS 基于蛋白质组学和脂质组学，证明了 ER 应激诱导的脂肪细胞分泌的外泌体（ATEx）协调了肝脏中的脂质动态。我们还注意到，ATEx 通过甘油和三酸酯在肝细胞中的初始积累引起肝脂肪变性、炎症和纤维化，从而导致 NASH。我们还确定了醛酮还原酶 1B7（Akr1b7），一种肝脏脂质代谢的关键介质，参与了 ATEx 介导的 NASH 诱导。值得注意的是，内质网应激诱导的 ATEx 中的 Akr1b7 缺乏强烈保护了小鼠肝脏免受 HFD 和 MCD 诱导的 NASH。我们的结果表明，ER 应激诱导的脂肪细胞分泌的 ATEx 通过向肝细胞传递外泌体 AKR1B7 并提高甘油水平来触发 NASH。这些发现表明了通过靶向 ATEx 来预防或管理肥胖引起的 NASH 的潜在治疗策略。
