Program in Molecular Medicine; Davis Lab
Amino Acids, Peptides, and Proteins | Cell Biology | Cells | Cellular and Molecular Physiology | Digestive System | Digestive System Diseases | Hepatology | Hormones, Hormone Substitutes, and Hormone Antagonists | Nucleic Acids, Nucleotides, and Nucleosides
SAB 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.
Apoptosis, Hepatology, P53, Sex hormones
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Copyright © 2019 American Society for Clinical Investigation. Final accepted manuscript posted as allowed by publisher's policy at https://www.jci.org/kiosks/terms.
DOI of Published Version
J Clin Invest. 2019 Sep 5. pii: 128289. doi: 10.1172/JCI128289. [Epub ahead of print] Link to article on publisher's site
The Journal of clinical investigation
Win S, Min RW, Chen CQ, Zhang J, Chen Y, Li M, Suzuki A, Abdelmalek MF, Wang Y, Aghajan M, Aung FW, Diehl AM, Davis RJ, Than TA, Kaplowitz N. (2019). Expression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injury. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1172/JCI128289. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1638
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