Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice

González‐Granillo, Marcela; Steffensen, Knut R.; Granados, Omar; Torres, Nimbe; Korach-André, Marion; Ortíz, Víctor; Aguilar-Salinas, C.; Jakobsson, Tomas; Dı́az-Villaseñor, Andrea; Loza‐Valdes, Angel; Hernández-Pando, Rogelio; Gustafsson, Jan‐Åke; Tovar, Armando R.

doi:10.1007/s00125-012-2599-9

Cited by 43 publications

(29 citation statements)

References 43 publications

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“…LXRα, as a subgroup of PPAR‐γ, regulates cholesterol homoeostasis through upregulating ABCA1 expression, which then stimulates cholesterol efflux from cells to plasma lipid‐free Apo‐A1 (Chinetti et al., ; Wade & Owen, ). Furthermore, it has been reported that the consumption of soybeans can be beneficial to lipid metabolism, the potential mechanism of which may be activating certain nuclear receptors, such as LXR (Gonzalez‐Granillo et al., ), but it is not known that whether genistein modulates cholesterol efflux through PPARγ/LXRα/ABCA1 pathway or not.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Zheng

Yin

et al. 2019

Journal of Food Science

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It has been reported that genistein could improve metabolic syndromes. Our study aimed to investigate the effects and potential mechanisms of genistein on improving cholesterol metabolism in HepG2 cell. HepG2 cells were cultured with 0, 0.01, 1.00, 10.00, and 50.00 µM genistein for 24 hr. The current results showed a dose‐dependent manner between genistein and intracellular contents of total cholesterol (TC), high‐density lipoprotein‐cholesterol (HDL‐C), and cellular apolipoprotein A1 (Apo‐A1) secretion. TC was increased by 25.69%, meanwhile HDL‐C and Apo‐A1 were decreased by 56.00% and 25.93%, respectively, when the dosage of genistein was 1.00 µM. Genistein dose‐dependently upregulated the protein and mRNA levels of sterol regulatory element binding proteins‐2 (SREBP‐2), as well as the mRNA levels of low‐density lipoprotein receptor (LDLR) and 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase (HMGCR), by 145.91%, 72.29%, 310.23%, and 123.08%, respectively, when we gave 1.00 µM genistein, indicating that intracellular cholesterol synthesis and absorption of exogenous cholesterol were increased. In addition, the mRNA levels of peroxisome proliferator‐activated receptor‐γ (PPARγ) and liver X receptor (LXRα), lowered by 58.23% and 34.86% at 0.01 µM genistein, were reduced in a dose‐dependent manner. LXRα and ATP‐binding cassette transporter A1 (ABCA1) protein levels were significantly (P < 0.05) decreased by 50.35% and 11.60% at 1.00 µM genistein, which indicated that cellular cholesterol efflux was inhibited. Taken together, our results suggested that genistein at dosage of more than 1.00 µM was able to increase the intracellular cholesterol levels by up regulating SREBP‐2/LDLR/HMGCR pathway and suppressing PPARγ/LXRα/ABCA1 pathway. Practical Application In this study, genistein appeared to be effective in reducing plasma cholesterol levels due to increase the intracellular cholesterol levels by upregulating cholesterol absorption through SREBP‐2/LDLR/HMGCR pathway, and also downregulating cholesterol efflux via PPARγ/LXRα/ABCA1 pathway in vitro. In addition, plasma cholesterol is regarded as the key indicator of atherosclerosis; therefore, we believe that our findings could be used for further exploration on a possible therapeutic application of genistein for atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

“…. potential mechanism of which may be activating certain nuclear receptors, such as LXR (Gonzalez-Granillo et al, 2012), but it is not known that whether genistein modulates cholesterol efflux through PPARγ /LXRα/ABCA1 pathway or not.…”

Section: Introductionmentioning

confidence: 99%

Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Zheng

Yin

et al. 2019

Journal of Food Science

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“…There is evidence that other bioactive compounds such as isoflavones have similar effects on LXR activity (González-Granillo et al 2012). It has been suggested that these compounds could regulate the activity of the enzyme adenosine monophosphate kinase (AMPK), and this in turn could modulate the phosphorylation state of LXR modifying its biological activity (González-Granillo et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Protein extraction and Western blotting were performed as previously reported (González-Granillo et al 2012). Briefly, primary rat hepatocytes were homogenized in lysis protein RIPA buffer and complete protease inhibitor cocktail tablets (Roche Applied Science, Germany).…”

Section: Protein Extraction and Western Blottingmentioning

confidence: 99%

Conjugated and free sterols from black bean (Phaseolus vulgaris L.) seed coats as cholesterol micelle disruptors and their effect on lipid metabolism and cholesterol transport in rat primary hepatocytes

et al. 2013

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Phytosterols have been widely studied for their cholesterol-lowering effect. Conjugated phytosterol forms have been found more active than free moieties. There are no reports about the sterol profile of black bean seed coats neither its effects on cholesterol metabolism. The aim of this research was to identify and quantify phytosterols from black bean seed coats and to determine their effects on cholesterol micellar solubility and on mRNA and key protein levels involved in lipid/cholesterol metabolism and cholesterol transport in primary rat hepatocytes. Free phytosterols, acylated steryl glycosides, and steryl glycosides were extracted from black bean seed coats. They were identified through HPLC-MS-TOF and quantified through HPLC equipped with UV-visible and evaporative light-scattering detectors. Free and conjugated phytosterols from the coats significantly increased the inhibitory effect of cholesterol micelle formation compared with stigmasterol, which was used as control (P \ 0.05). In addition, phytosterols of black bean seed coat decreased lipogenesis by the downregulation of lipogenic proteins such as sterol regulatory element-binding protein 1 and fatty acid synthesis (FAS) in primary rat hepatocytes. Regarding b-oxidation, phytosterols upregulated the expression of carnitine palmitoyltransferase I and promoted the b-oxidation of long-chain fatty acids. Phytosterols inhibited cholesterol micellar solubility and reduced the activation of the liver X receptor, decreasing hepatic FAS and promoting hepatic b-oxidation of long-chain fatty acids.

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“…Unfortunately, the trial was terminated due to adverse central nervous system effects. [19][20][21] LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others [22][23][24][25][26][27][28] (Fig. 1).…”

mentioning

confidence: 99%

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Nian

Gan

Tan

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC 50 value of 6.4 µM against LXRα and an IC 50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists.Key words liver X receptor α; liver X receptor β; antagonistic activity Nuclear receptors (NRs) are ligand-activated transcription factors that coordinate gene expression in response to the modulation of metabolism, development, proliferation, and inflammation.1,2) Liver X receptors (LXRs) belonging to the NR superfamily are activated by specific oxidized forms of cholesterol and intermediate products of the cholesterol biosynthetic pathway. 1,3,4) There are two LXR isoforms in mammals, termed LXRα and LXRβ. LXRα is abundantly expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRβ is more ubiquitously expressed, with particularly high levels in the developing brain. [5][6][7][8] Both isoforms share almost 80% homology of their amino acid sequences in their DNA-binding domain and ligand-binding domain. 5,7)The LXR consists of four domains: N-terminal ligandindependent activation function domain (AF-1); DNA-binding domain (DBD); hydrophobic ligand-binding domain (LBD); and C-terminal ligand-dependent transactivation sequence (AF-2).5,9,10) By forming heterodimers with retinoid X receptors (RXRs), LXRs bind to LXR response elements (LXREs) in the promoter or enhancer elements of LXR target genes. The activation of LXR-RXR heterodimers not only induces the expression of a variety of target genes (CYP7A, ABCA1, SREBP-1) that are involved in lipid and glucose metabolism, but also results in the inhibition of genes encoding inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ. 1,[11][12][13][14][15] In the last decade, GlaxoSmithKline and other several pharmaceutical companies have been active in developing synthetic LXR agonists (Fig. 1). T0901317 (1, Tularik) and GW3965 (2, GSK) exhibit nonselectivity for LXRα and LXRβ with high affinity.11,16-18) The first compound to enter the clinic was LXR-623 (3, Wyeth), an LXRα/β partial agonist for the potential treatment of atherosclerosis and dyslipidemia. Unfortunately, the trial was terminated due to adverse central nervous system effects.19-21) LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others 22-28) (Fig. 1).SR-9238 was the first selective synthetic LXR inverse agonist that displays a degree of LXRβ selectivity with an IC 50 value of 214 nM for LXRα and 43 nM for LXRβ, and this compound effectively suppressed hepatic lipogenesis, inflammation, and hepatic lipid...

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Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice

Abstract: Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRβ, resulting in different biological effects for each LXR isoform.

Cited by 43 publications

References 43 publications

Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Effect of Genistein on Cholesterol Metabolism‐Related Genes in HepG2 Cell

Conjugated and free sterols from black bean (Phaseolus vulgaris L.) seed coats as cholesterol micelle disruptors and their effect on lipid metabolism and cholesterol transport in rat primary hepatocytes

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

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