The Role of Sulfotransferases in Liver Diseases

Abstract

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes that catalyze the transfer of a sulfonate group from the universal sulfate donor 3'-phosphoadenosine-5'-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 4α 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 STATEMENT: Sulfotransferases (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.

Fig. 1.

Diagram showing the sex- and tissue-specific effect of Sult1a1 on the susceptibility to ABP. In male mice, more ABP was transported into bladder from the liver because of the androgen-dependent suppression of SULT1A1, leading to an increased sensitivity of bladder to ABP-induced carcinogenesis. In female mice, a relatively high expression of SULT1A1 leads to increased sensitivity of the liver to the exposure to ABP and ABP-sulfate. dG-C8-ABP, N-(deoxyguanosin-8-yl)-4-aminobiphenyl.

Fig. 2.

Summary of the role of SULT2B1B in liver diseases. Overexpression of SULT2B1b promotes the progression of HCC via the activation of the β-catenin/matrix metalloproteinase 7 (MMP7) pathway in hepatocytes. Overexpression of SULT2B1b increases the sulfonation and deactivation of oxysterols and thereby dampens the lipogenic function of LXR and decreases the serum and hepatic lipids. In addition to inhibiting lipogenesis, SULT2B1b and its metabolic byproduct cholesterol sulfate exhibit major activity in inhibiting hepatic gluconeogenesis and relieving metabolic liver disease by suppressing the gluconeogenic activity of HNF4α, a transcription factor that positively regulates SULT2B1b gene expression. The induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Overexpression of SULT2B1b sensitized mice to APAP-induced liver injury, and overexpression of Hnf4α increases the sensitivity to APAP-induced hepatotoxicity in a Sult2b1b-dependent manner.