Cytosolic sulfotransferase 2B1b (SULT2B1b) catalyzes the sulfation of 3-hydroxysteroids and functions as a selective cholesterol and oxysterol sulfotransferase. Activation of liver X receptors (LXRs) by oxysterols has been known to be an antiproliferative factor. Overexpression of SULT2B1b impairs LXR's response to oxysterols, by which it regulates lipid metabolism. The aim of this study was to investigate in vivo and in vitro effects of SULT2B1b on liver proliferation and the underlying mechanisms. Primary rat hepatocytes and C57BL/6 mice were infected with adenovirus encoding SULT2B1b. Liver proliferation was determined by measuring the proliferating cell nuclear antigen (PCNA) immunostaining labeling index. The correlation between SULT2B1b and PCNA expression in mouse liver tissues was determined by double immunofluorescence. Gene expressions were evaluated by quantitative real-time PCR and Western blot analysis. SULT2B1b overexpression in mouse liver tissues increased PCNApositive cells in a dose-and time-dependent manner. The increased expression of PCNA in mouse liver tissues was only observed in the SULT2B1b transgenic cells. Small interference RNA SULT2B1b significantly inhibited cell cycle regulatory gene expressions in primary rat hepatocytes. LXR activation by T0901317 effectively suppressed SULT2B1b-induced gene expression in vivo and in vitro. SULT2B1b may promote hepatocyte proliferation by inactivating oxysterol/LXR signaling. 25-hydroxycholesterol; liver proliferation; liver X receptors; oxysterol; proliferating cell nuclear antigen CYTOSOLIC SULFOTRANSFERASES (SULTs) sulfate small molecules, such as hormones, neurotransmitters, bioamines, and therapeutic drugs (13,14,44). The human SULT gene superfamily is composed of at least five families, one of which (SULT2) is primarily engaged in the sulfoconjugation of neutral steroids and sterols (37). The SULT2 family contains two subfamilies, SULT2A1 and SULT2B1, and the SULT2B1 subfamily is additionally divided into two isoforms, SULT2B1a and SULT2B1b (23). SULT2B1b expresses in multiple human tissues, including placenta, prostate, breast, skin, lung, small intestine, liver, and platelets (15,21,22,24,31,35,49). SULT2B1b effectively catalyzes the sulfation of 3-hydroxysteroids and functions as a selective cholesterol and oxysterol sulfotransferase (1,12,16,17,31,36). Oxysterols such as 24-hydroxycholesterol and 25-hydroxycholesterol (25HC) have been identified as endogenous ligands for activation of liver X receptors (LXRs) in vitro and in vivo (1, 3, 7, 12). Therefore, it is possible that oxysterol sulfation by SULT2B1b could be an important regulatory mechanism in the LXR signaling pathway.LXRs are nuclear receptors that play a crucial role in the control of lipid metabolism (38). LXRs enhance fatty acid synthesis by activating the transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c), which in turn activates lipogenic genes (6, 32). LXRs also directly stimulate the transcription of certain lipogenic genes, inc...