TY - JOUR AU - Win, Sanda AU - Min, Robert W.M. AU - Chen, Christopher Q. AU - Zhang, Jun AU - Chen, Yibu AU - Li, Meng AU - Suzuki, Ayako AU - Abdelmalek, Manal F. AU - Wang, Ying AU - Aghajan, Mariam AU - Aung, Filbert W.M. AU - Diehl, Anna Mae AU - Davis, Roger J. AU - Than, Tin A. AU - Kaplowitz, Neil T1 - Expression of mitochondrial membrane–linked SAB determines severity of sex-dependent acute liver injury PY - 2019/12/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI128289 VL - 129 IS - 12 UR - https://doi.org/10.1172/JCI128289 SP - 5278 EP - 5293 PB - The American Society for Clinical Investigation ER -