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Expression of mitochondrial membrane–linked SAB determines severity of sex-dependent acute liver injury
Sanda Win, … , Tin A. Than, Neil Kaplowitz
Sanda Win, … , Tin A. Than, Neil Kaplowitz
Published September 5, 2019
Citation Information: J Clin Invest. 2019;129(12):5278-5293. https://doi.org/10.1172/JCI128289.
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Research Article Hepatology

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

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Abstract

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.

Authors

Sanda Win, Robert W.M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W.M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz

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Figure 7

miR34a-5p modulates SAB expression and hepatotoxicity.

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miR34a-5p modulates SAB expression and hepatotoxicity.
miR34afl/fl fema...
miR34afl/fl female mice received AAV8-TBG-GFP or AAV8-TBG-Cre via tail-vein injection to generate miR34afl/fl or miR34aiΔHep mice. (A and B) Two weeks later, levels of miR34a-5p expression, SAB and PHB1 expression in mitochondria, and p53, SIRT1, and GAPDH expression in liver extract were determined. n = 5 mice/group. *P < 0.05 versus the AAV8-GFP group, by unpaired, 2-tailed Student’s t test. Data are presented as the mean ± SEM. (C) Overnight-fasted mice received APAP or GalN/TNF, and liver histology was performed and serum ALT levels determined 6 hours (GalN/TNF) and 24 hours (APAP) later. Representative H&E-stained images are shown. Scale bars: 100 μm. n = 5 mice/group. *P < 0.05 versus the AAV8-GFP group, by unpaired, 2-tailed Student’s t test. Data are presented as the mean ± SD. (D) miR34aiΔHep (miR34afl/fl plus AAV8-TBG-Cre) female mice received GalNAc-control or Sab-ASO for 2 weeks to deplete hepatocellular SAB expression. Overnight-fasted mice then received APAP or GalN/TNF, and liver histology was performed and serum ALT levels determined 6 hours (GalN/TNF) and 24 hours (APAP) later. Representative H&E-stained images are shown. Scale bars: 100 μm. n = 5 mice/group. *P < 0.05 versus GalNAc-control-ASO, by unpaired, 2-tailed Student’s t test. Data are presented as the mean ± SD. (E) Schematic presentation of the ERα/p53/miR34a-5p axis of regulation of SAB expression.

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