An Unexpected Role of Cholesterol Sulfotransferase and its Regulation in Sensitizing Mice to Acetaminophen-Induced Liver Injury

An, Yunqi; Wang, Pengcheng; Xu, Pengfei; Tung, Hung‐Chun; Xie, Yang; Kirisci, Levent; Xu, Meishu; Tian, Xin; Ma, Xiaochao; Xie, Wen

doi:10.1124/mol.118.114819

Cited by 9 publications

(5 citation statements)

References 49 publications

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“…This is a somewhat surprising result considering that sulfation is generally considered to be a metabolic pathway that detoxifies APAP. Consistent with our previous finding that SULT2B1b is a transcriptional target of HNF4a, Hnf4a overexpression also sensitized mice to APAPinduced hepatotoxicity in a Sult2b1b-dependent manner, indicating that the HNF4a-SULT2B1b axis plays a unique role in APAP-induced hepatotoxicity and that SULT2B1b induction might be a risk factor for APAP toxicity (An et al, 2019).…”

Section: Sult2b1bsupporting

confidence: 91%

“…In a recent study, we uncovered an unexpected role for SULT2B1b in APAP-induced liver injury. Hepatic overexpression of SULT2b1b enhanced the sensitivity of mice to APAP-induced liver injury, whereas ablation of the Sult2B1b in mice conferred resistance to the APAP hepatotoxicity (An et al, 2019). This is a somewhat surprising result considering that sulfation is generally considered to be a metabolic pathway that detoxifies APAP.…”

Section: Sult2b1bmentioning

confidence: 99%

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The Role of Sulfotransferases in Liver Diseases

Xie

2020

Drug Metabolism and Disposition

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The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes that catalyze the transfer of a sulfonate group from the universal sulfate donor 39-phosphoadenosine-59-phosphosulfate to a nucleophilic group of their substrates to generate hydrophilic products. Sulfation has a major effect on the chemical and functional homeostasis of substrate chemicals. SULTs are widely expressed in metabolically active or hormonally responsive tissues, including the liver and many extrahepatic tissues. The expression of SULTs exhibits isoform-, tissue-, sex-, and development-specific regulations. SULTs display a broad range of substrates including xenobiotics and endobiotics. The expression of SULTs has been shown to be transcriptionally regulated by members of the nuclear receptor superfamily, such as the peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, liver X receptors, farnesoid X receptor, retinoid-related orphan receptors, estrogen-related receptors, and hepatocyte nuclear factor 4a. These nuclear receptors can be activated by numerous xenobiotics and endobiotics, such as fatty acids, bile acids, and oxysterols, many of which are substrates of SULTs. Due to their metabolism of xenobiotics and endobiotics, SULTs and their regulations are implicated in the pathogenesis of many diseases. This review is aimed to summarize the central role of major SULTs, including the SULT1 and SULT2 subfamilies, in the pathophysiology of liver and liver-related diseases. SIGNIFICANCE STATEMENTSulfotransferases (SULTs) are indispensable in the homeostasis of xenobiotics and endobiotics. Knowing SULTs and their regulations are implicated in human diseases, it is hoped that genetic or pharmacological manipulations of the expression and/or activity of SULTs can be used to affect the clinical outcome of diseases.

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Section: Sult2b1bsupporting

confidence: 91%

Section: Sult2b1bmentioning

confidence: 99%

The Role of Sulfotransferases in Liver Diseases

Xie

2020

Drug Metabolism and Disposition

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“…CS-deficient mice displayed a heightened sensitivity to self-antigens (Wang et al, 2016). Systemic up-regulation of SULT2B1b inhibited lipogenesis by sulfonating and deactivating the liver X receptor (LXR)-activating oxysterols in LDLR −/− mice (Bai et al, 2012) and overexpression of hepatic SULT2B1b sensitized the mice to drug-induced liver damage (An et al, 2019) and inhibition of gluconeogenesis (Shi et al, 2014).…”

Section: Sult2b1a and Sult2b1bmentioning

confidence: 99%

Cholesterol and oxysterol sulfates: Pathophysiological roles and analytical challenges

Sanchez

Pontini

Marinozzi

et al. 2020

British J Pharmacology

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Cholesterol and oxysterol sulfates are important regulators of lipid metabolism, inflammation, cell apoptosis, and cell survival. Among the sulfate-based lipids, cholesterol sulfate (CS) is the most studied lipid both quantitatively and functionally. Despite the importance, very few studies have analysed and linked the actions of oxysterol sulfates to their physiological and pathophysiological roles. Overexpression of sulfotransferases confirmed the formation of a range of oxysterol sulfates and their antagonistic effects on liver X receptors (LXRs) prompting further investigations how are the changes to oxysterol/oxysterol sulfate homeostasis can contribute to LXR activity in the physiological milieu. Here, we aim to bring together for novel roles of oxysterol sulfates, the available techniques and the challenges associated with their analysis. Understanding the oxysterol/oxysterol sulfate levels and their pathophysiological mechanisms could lead to new therapeutic targets for metabolic diseases.

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“…Compared with the well identified f u n c t i o n s o f H N F 4 α , t h e u n d e r l y i n g m o l e c u l a r mechanisms of HNF4α in drug-induced liver damage is still controversial. Overexpression of HNF4α sensitizes mice or primary hepatocytes to acetaminophen-induced liver injury (19). Meanwhile, degradation of HNF4α has been shown to aggravate steatosis and tumorigenesis in human livers induced by perfluorooctanoic acid and perfluorooctanesulfonic acid (20).…”

Section: Introductionmentioning

confidence: 99%