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dc.contributor.authorWin, Sanda
dc.contributor.authorMin, Robert W. M.
dc.contributor.authorChen, Christopher Q.
dc.contributor.authorZhang, Jun
dc.contributor.authorChen, Yibu
dc.contributor.authorLi, Meng
dc.contributor.authorSuzuki, Ayako
dc.contributor.authorAbdelmalek, Manal F.
dc.contributor.authorWang, Ying
dc.contributor.authorAghajan, Mariam
dc.contributor.authorAung, Filbert W. M.
dc.contributor.authorDiehl, Anna Mae
dc.contributor.authorDavis, Roger J.
dc.contributor.authorThan, Tin A.
dc.contributor.authorKaplowitz, Neil
dc.date2022-08-11T08:08:24.000
dc.date.accessioned2022-08-23T15:53:43Z
dc.date.available2022-08-23T15:53:43Z
dc.date.issued2019-09-05
dc.date.submitted2019-10-09
dc.identifier.citation<p>J Clin Invest. 2019 Sep 5. pii: 128289. doi: 10.1172/JCI128289. [Epub ahead of print] <a href="https://doi.org/10.1172/JCI128289">Link to article on publisher's site</a></p>
dc.identifier.issn0021-9738 (Linking)
dc.identifier.doi10.1172/JCI128289
dc.identifier.pmid31487267
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29409
dc.description.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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31487267&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 2019 American Society for Clinical Investigation. Final accepted manuscript posted as allowed by publisher's policy at https://www.jci.org/kiosks/terms.
dc.subjectApoptosis
dc.subjectHepatology
dc.subjectP53
dc.subjectSex hormones
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectDigestive System
dc.subjectDigestive System Diseases
dc.subjectHepatology
dc.subjectHormones, Hormone Substitutes, and Hormone Antagonists
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleExpression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injury
dc.typeAccepted Manuscript
dc.source.journaltitleThe Journal of clinical investigation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2648&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1638
dc.identifier.contextkey15521706
refterms.dateFOA2022-08-23T15:53:43Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/1638
dc.contributor.departmentDavis Lab
dc.contributor.departmentProgram in Molecular Medicine


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