Sulfation of 25-hydroxycholesterol by SULT2B1b decreases cellular lipids via the LXR/SREBP-1c signaling pathway in human aortic endothelial cells

Bai, Qianming; Xu, Leyuan; Kakiyama, Genta; Runge‐Morris, Melissa; Hylemon, Phillip B.; Li, Yin; Pandak, William M.; Ren, Shuling

doi:10.1016/j.atherosclerosis.2010.11.021

Cited by 64 publications

(75 citation statements)

References 32 publications

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“…Consistently, the TCPOBOPinduced reduction of lipogenic genes is abolished in Sult2B1b knockout mice [78] . Liver-specific overexpression of Sult2B1b, either by adenoviral delivery or transgenic strategy, ameliorates dyslipidemia in a diabetic mouse model [84,85] . In addition to deactivating LXR ligands, the products of sulfonation, such as 25-hydroxycholesterol-3-sulfate, have been reported to decrease lipid accumulation and inflammation [86][87][88][89] .…”

Section: Car In Energy Metabolismmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

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Section: Car In Energy Metabolismmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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“…However, addition of 25HC3S to primary hepatocytes downregulates the expression of key enzymes involved in lipid metabolism and decreases lipid biosynthesis by inactivating the LXR/SREBP-1c signaling pathway in hepatocytes and macrophages (38,52,58). Furthermore, overexpression of SULT2B1b decreases intracellular lipid levels in human aortic cells (3).…”

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confidence: 99%

25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages

Shen²,

Ma³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The nuclear receptor peroxisome proliferator-activated receptors (PPARs) are important in regulating lipid metabolism and inflammatory responses in macrophages. Activation of PPAR␥ represses key inflammatory response gene expressions. Recently, we identified a new cholesterol metabolite, 25-hydroxycholesterol-3-sulfate (25HC3S), as a potent regulatory molecule of lipid metabolism. In this paper, we report the effect of 25HC3S and its precursor 25-hydroxycholesterol (25HC) on PPAR␥ activity and on inflammatory responses. Addition of 25HC3S to human macrophages markedly increased nuclear PPAR␥ and cytosol IB and decreased nuclear NF-B protein levels. PPAR␥ response element reporter gene assays showed that 25HC3S significantly increased luciferase activities. PPAR␥ competitor assay showed that the Ki for 25HC3S was ϳ1 M, similar to those of other known natural ligands. NF-B-dependent promoter reporter gene assays showed that 25HC3S suppressed TNF␣-induced luciferase activities only when cotransfected with pcDNAI-PPAR␥ plasmid. In addition, 25HC3S decreased LPSinduced expression and release of IL-1␤. In the PPAR␥-specific siRNA transfected macrophages or in the presence of PPAR␥-specific antagonist, 25HC3S failed to increase IB and to suppress TNF␣ and IL-1␤ expression. In contrast to 25HC3S, its precursor 25HC, a known liver X receptor ligand, decreased nuclear PPAR␥ and cytosol IB and increased nuclear NF-B protein levels. We conclude that 25HC3S acts in macrophages as a PPAR␥ ligand and suppresses inflammatory responses via the PPAR␥/IB/NF-B signaling pathway.peroxisome proliferator-activated receptor-␥; oxysterols; oxysterol sulfation; cholesterol metabolites; inflammatory response; macrophages; nuclear factor-B signaling pathway MACROPHAGES ARE THE KEY CELLULAR PLAYERS in the pathogenesis of atherosclerosis. In the early stage of atherosclerosis, macrophages in arterial walls accumulate lipids. These lipid-loaded macrophages, termed foam cells, are characteristic of a reversible early cellular phase of atherosclerotic lesions. Progressive lipid accumulation leads to further escalation of inflammatory responses and infiltration of inflammatory cells (26). Through this process, early cellular lesions are transformed to late, fibrous, atherosclerotic plaques. Physiological or pharmacological maneuvers that reduce macrophage lipids and inflammatory responses may be effective in preventing or reversing atherosclerosis.Nuclear receptors are ligand-activated transcription factors that regulate the expression of target genes to affect processes as diverse as reproduction, inflammation, development, and metabolism (17). Nuclear receptor peroxisome proliferatoractivated receptors (PPARs) play major roles in the regulation of lipid metabolism, glucose homeostasis, and inflammatory processes and may be ideal targets for therapeutic management strategies for cardiovascular diseases (4,6,11,16,23,42). PPAR␥ appears particularly important in regulating genes involved in lipid metabolism and inflammation (1,8,20,21). The PPAR␥...

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“…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.…”

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confidence: 99%

“…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).…”

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Cytosolic sulfotransferase 2B1b promotes hepatocyte proliferation gene expression in vivo and in vitro

Zhang

Bai

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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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...

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Sulfation of 25-hydroxycholesterol by SULT2B1b decreases cellular lipids via the LXR/SREBP-1c signaling pathway in human aortic endothelial cells

Cited by 64 publications

References 32 publications

Deciphering the roles of the constitutive androstane receptor in energy metabolism

Deciphering the roles of the constitutive androstane receptor in energy metabolism

25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages

Cytosolic sulfotransferase 2B1b promotes hepatocyte proliferation gene expression in vivo and in vitro

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