Expression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injury

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.

Keywords: Apoptosis; Hepatology; P53; Sex hormones.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen
  • Animals
  • Apoptosis
  • Cell Death / drug effects
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Liver Failure, Acute / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Mitochondria, Liver / metabolism
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Necrosis
  • RNA, Messenger / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Esr1 protein, mouse
  • Estrogen Receptor alpha
  • MIRN34a microRNA, mouse
  • Membrane Proteins
  • MicroRNAs
  • Mitochondrial Proteins
  • RNA, Messenger
  • Sab protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Acetaminophen