Enhanced steatosis by nuclear receptor ligands: A study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile

Moya, Marta; Gómez-Lechón, Marı́a José; Castell, José V.; Jover, Ramiro

doi:10.1016/j.cbi.2010.01.008

Cited by 74 publications

(57 citation statements)

References 71 publications

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“…In the current study, we showed that, as a potent inducer of SLC13A5, RIF enhances lipid accumulation in HPH. These results are in agreement with a previous report, in that by screening the steatogenic potential of 76 different nuclear receptor ligands, 18% of the examined ligands, including RIF, exhibited enhanced lipid accumulation in human liver cells (Moya et al, 2010). On the other hand, ketoconazole, an established inhibitor of PXR, improved the metabolic function of high-fat diet-fed mice (Huang et al, 2007;He et al, 2013).…”

Section: Discussionsupporting

confidence: 93%

SLC13A5 Is a Novel Transcriptional Target of the Pregnane X Receptor and Sensitizes Drug-Induced Steatosis in Human Liver

Garzel

et al. 2015

Mol Pharmacol

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The solute carrier family 13 member 5 (SLC13A5) is a sodiumcoupled transporter that mediates cellular uptake of citrate, which plays important roles in the synthesis of fatty acids and cholesterol. Recently, the pregnane X receptor (PXR, NR1I2), initially characterized as a xenobiotic sensor, has been functionally linked to the regulation of various physiologic processes that are associated with lipid metabolism and energy homeostasis. Here, we show that the SLC13A5 gene is a novel transcriptional target of PXR, and altered expression of SLC13A5 affects lipid accumulation in human liver cells. The prototypical PXR activator rifampicin markedly induced the mRNA and protein expression of SLC13A5 in human primary hepatocytes. Utilizing cell-based luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays, we identified and functionally characterized two enhancer modules located upstream of the SLC13A5 gene transcription start site that are associated with regulation of PXR-mediated SLC13A5 induction. Functional analysis further revealed that rifampicin can enhance lipid accumulation in human primary hepatocytes, and knockdown of SLC13A5 expression alone leads to a significant decrease of the lipid content in HepG2 cells. Overall, our results uncover SLC13A5 as a novel target gene of PXR and may contribute to drug-induced steatosis and metabolic disorders in humans.

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Section: Discussionsupporting

confidence: 93%

SLC13A5 Is a Novel Transcriptional Target of the Pregnane X Receptor and Sensitizes Drug-Induced Steatosis in Human Liver

Garzel

et al. 2015

Mol Pharmacol

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“…Because cholesterol addition had no effect on the lipid content of control hepatoma cells, this observation raised the possibility that the inability of POR-suppressed cells to eliminate cholesterol might lead to the generation of oxysterols in these cells. Oxysterols serve as potent ligands for the liver X receptor (LXR), which stimulates triglyceride synthesis, accumulation, and hepatic steatosis (Kalaany and Mangelsdorf, 2006;Moya et al, 2010). To test this hypothesis, the abundance of three oxysterols whose formation does not require cytochrome P450 reductase (22␤-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol) was determined by gas chromatography-mass spectrometry in control and POR-suppressed hepatoma cells.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Cytochrome P450 Reductase (POR) Expression in Hepatoma Cells Replicates the Hepatic Lipidosis Observed in Hepatic POR-Null Mice

Porter¹,

Banerjee²,

Stolarczyk³

et al. 2011

Drug Metab Dispos

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“…ER agonists have been linked to the development of hepatotoxicity such as hepatic steatosis due to their ability to inhibit respiration leading to increased accumulation of triglycerides within the liver (Bandypadhyay et al, 2006;Foster, 2012;Lelliot et al, 2005;Moya et al, 2010;Shimizu et al, 2007).…”

Section: Oestrogen Receptor (Er)mentioning

confidence: 99%

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

Mellor

Steinmetz

Cronin

2015

Critical Reviews in Toxicology

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The development of Adverse Outcome Pathways (AOPs) is becoming a key component of 21 st century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organised toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This paper reviews and summarises the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor, and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome.

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Enhanced steatosis by nuclear receptor ligands: A study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile

Cited by 74 publications

References 71 publications

SLC13A5 Is a Novel Transcriptional Target of the Pregnane X Receptor and Sensitizes Drug-Induced Steatosis in Human Liver

SLC13A5 Is a Novel Transcriptional Target of the Pregnane X Receptor and Sensitizes Drug-Induced Steatosis in Human Liver

Suppression of Cytochrome P450 Reductase (POR) Expression in Hepatoma Cells Replicates the Hepatic Lipidosis Observed in Hepatic POR-Null Mice

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

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