Expression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injury
Min, Robert W. M.
Chen, Christopher Q.
Abdelmalek, Manal F.
Aung, Filbert W. M.
Diehl, Anna Mae
Davis, Roger J.
Than, Tin A.
UMass Chan AffiliationsDavis Lab
Program in Molecular Medicine
Document TypeAccepted Manuscript
Amino Acids, Peptides, and Proteins
Cellular and Molecular Physiology
Digestive System Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Nucleic Acids, Nucleotides, and Nucleosides
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AbstractSAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERalpha to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF/galactosamine. In contrast, ERalpha agonist increased p53 and miR34a-5p which decreased SAB expression and hepatotoxicity in males. Hepatocyte-specific deletion of miR34a also increased severity of liver injury in females, which was prevented by GalNAc-ASO knockdown of Sab. Similar to mice, premenopausal human females also expressed high hepatic p53 and low SAB levels while age-matched males expressed low p53 and high SAB levels, but there was no sex difference of SAB expression in postmenopause. In conclusion, the level of SAB expression determined the severity of JNK dependent liver injury. Females expressed low hepatic SAB protein levels due to an ERalpha-p53-miR34a pathway which repressed SAB expression, accounting for resistance to liver injury.
J Clin Invest. 2019 Sep 5. pii: 128289. doi: 10.1172/JCI128289. [Epub ahead of print] Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29409
RightsCopyright © 2019 American Society for Clinical Investigation. Final accepted manuscript posted as allowed by publisher's policy at https://www.jci.org/kiosks/terms.