PT  - JOURNAL ARTICLE
AU  - Yunqi An
AU  - Pengcheng Wang
AU  - Pengfei Xu
AU  - Hung-chun Tung
AU  - Yang Xie
AU  - Levent Kirisci
AU  - Meishu Xu
AU  - Songrong Ren
AU  - Xin Tian
AU  - Xiaochao Ma
AU  - Wen Xie
TI  - An unexpected role of cholesterol sulfotransferase and its regulation in sensitizing mice to acetaminophen induced liver injury
AID  - 10.1124/mol.118.114819
DP  - 2019 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.114819
4099  - http://molpharm.aspetjournals.org/content/early/2019/04/03/mol.118.114819.short
4100  - http://molpharm.aspetjournals.org/content/early/2019/04/03/mol.118.114819.full
AB  - Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. The sulfotransferase-mediated sulfation of APAP is widely believed to be a protective mechanism to attenuate the hepatotoxicity of APAP. The cholesterol sulfotransferase SULT2B1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol sulfate. SULT2B1b can be transcriptionally and positively regulated by the hepatic nuclear factor 4α (HNF4α). In this study, we uncovered an unexpected role for SULT2B1b in APAP toxicity. Hepatic overexpression of SULT2B1b sensitized mice to APAP-induced liver injury, whereas ablation of the Sult2B1b gene in mice conferred resistance to the APAP hepatotoxicity. Consistent with the notion that Sult2B1b is a transcriptional target of HNF4α, overexpression of HNF4α sensitizes mice or primary hepatocytes to APAP-induced hepatotoxicity in a Sult2B1b dependent manner. We conclude that the HNF4α-SULT2B1b axis has a unique role in APAP-induced acute liver injury, and SULT2B1b induction might be a risk factor for APAP hepatotoxicity.