Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA.
Gastroenterology and Hepatology.
J Clin Invest. 2020 Aug 3;130(8):4320-4330. doi: 10.1172/JCI133051.
Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.
2 型糖尿病与非酒精性脂肪性肝炎（NASH）中的进行性坏死性炎症和纤维化密切相关。在长期高血糖的情况下，会积累晚期糖基化终产物（AGEs），但导致加速肝纤维化的机制途径尚未得到很好的定义。在这项研究中，我们表明，AGEs 清除受体AGER1 在 NASH 和糖尿病患者以及我们的 NASH 模型中下调，而促炎受体 RAGE 则被诱导。这些发现与通过 NADPH 氧化酶 4 引起的坏死性炎症、纤维化和促氧化活性有关。体内肝细胞中 AGEs 或 RAGE 缺失的抑制作用逆转了这些影响。我们证明，通过 cullin 3 的 neddylation 对 NRF2 的失调与 AGER1 的下调有关，并且通过体内使用腺相关病毒介导的方法在肝细胞中诱导 NRF2 逆转了 AGER1 的下调，降低了 AGEs 的水平，并改善了高 AGEs 饮食小鼠的促炎和纤维化反应。在 NASH 和糖尿病或胰岛素抵抗患者中，低 AGER1 水平与肝细胞气球样变性和胆管反应有关。总的来说，肝脏中长时间暴露于 AGEs 会促进 NASH 中 AGER1/RAGE 失衡以及随后的氧化还原、炎症和纤维化活性。
