USC Research Center for Liver Disease, Keck School of Medicine, University of Southern California (USC), Los Angeles, California, USA.
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China.
J Clin Invest. 2019 Dec 2;129(12):5278-5293. doi: 10.1172/JCI128289.
SH3 domain-binding protein that preferentially associates with Btk (SAB) is an outer-membrane docking protein for JNK-mediated impairment of mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. The current study demonstrates that an increase in SAB expression enhanced the severity of acetaminophen-induced (APAP-induced) liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression compared with male mice. The mechanism of SAB repression involved a pathway from ERα to p53 expression that induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, thereby repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB expression in female mice, leading to increased injury from APAP and TNF/galactosamine. In contrast, an ERα agonist increased p53 and miR34a-5p, which decreased SAB expression and hepatotoxicity in male mice. Hepatocyte-specific deletion of miR34a also increased the severity of liver injury in female mice, which was prevented by GalNAc-ASO knockdown of Sab. Similar to mice, premenopausal women expressed elevated levels of hepatic p53 and low levels of SAB, whereas age-matched men expressed low levels of p53 and high levels of SAB, but there was no difference in SAB expression between the sexes in the postmenopausal stage. In conclusion, SAB expression levels determined the severity of JNK-dependent liver injury. Female mice expressed low levels of hepatic SAB protein because of the ERα/p53/miR34a pathway, which repressed SAB expression and accounted for the resistance to liver injury seen in these females.
优先与 Btk（SAB）结合的 SH3 结构域结合蛋白是一种 JNK 介导的线粒体功能障碍的外膜对接蛋白。肝细胞中 Sab 的缺失可抑制持续的 JNK 激活和细胞死亡。本研究表明，SAB 表达增加会加重醋氨酚（APAP）诱导的肝损伤。与雄性小鼠相比，雌性小鼠对肝损伤具有抗性，且肝 SAB 蛋白表达明显降低。SAB 抑制的机制涉及一条从 ERα 到 p53 表达的途径，该途径诱导了 miR34a-5p。miR34a-5p 靶向 Sab mRNA 编码区，从而抑制 SAB 表达。他莫昔芬或 p53 敲低减少了 miR34a-5p 并增加了雌性小鼠中的 SAB 表达，导致 APAP 和 TNF/半乳糖胺引起的损伤增加。相反，ERα 激动剂增加了 p53 和 miR34a-5p，从而减少了雄性小鼠中的 SAB 表达和肝毒性。miR34a 的肝细胞特异性缺失也增加了雌性小鼠肝损伤的严重程度，而 GalNAc-ASO 敲低 Sab 则可预防这种情况。与小鼠相似，绝经前妇女的肝组织中 p53 表达升高，SAB 表达降低，而年龄匹配的男性 p53 表达降低，SAB 表达升高，但绝经后阶段男女之间的 SAB 表达没有差异。总之，SAB 表达水平决定了 JNK 依赖性肝损伤的严重程度。雌性小鼠肝组织中 SAB 蛋白水平较低，原因是 ERα/p53/miR34a 通路抑制了 SAB 表达，这解释了雌性小鼠对肝损伤的抵抗力。
