Liver X receptors link lipid metabolism and inflammation

Schulman, Ira G.

doi:10.1002/1873-3468.12702

Cited by 166 publications

(167 citation statements)

References 117 publications

(192 reference statements)

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“…7 C ). Because several DEG are targets of the liver X receptor (LXR) (32), we sought to evaluate whether indole regulated the hepatic concentration of oxysterols that are key ligands for LXR. Interestingly, we found that among the panel of 10 oxysterols analyzed (Supplemental Table 4), the concentration of 4β-hydroxycholesterol was higher in the liver of mice treated with indole and LPS compared to mice treated with LPS alone (Fig.…”

Section: Resultsmentioning

confidence: 99%

The gut microbiota metabolite indole alleviates liver inflammation in mice

et al. 2018

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The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p-cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision-cut liver slices prepared from control mice, Kupffer cell (KC)-depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose-dependently reduced the LPS-induced up-regulation of proinflammatory mediators at both mRNA and protein levels in precision-cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain-containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF-κB pathway and downstream proinflammatory gene up-regulation. Indole also prevented LPS-induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β-hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.-B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice.

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Section: Resultsmentioning

confidence: 99%

The gut microbiota metabolite indole alleviates liver inflammation in mice

et al. 2018

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“…In addition , LXRα has anti-inflammatory activity through inhibition of NF-κB signaling pathway. 46 These above effects further support that MsrA has pleiotropic regulatory functions in HDL metabolism and inflammation, which largely relied on LXRα-upregulation.…”

Section: Discussionmentioning

confidence: 72%

“…It has been confirmed that ATP-binding cassette transporters, ABCA1 and ABCG5/8 are direct LXRα target genes. 46 Hepatic ABCA1 functions to export cellular cholesterol to lipid-free apoAI during the biogenesis of HDL, 47 and ABCG5 and ABCG8 form heterodimers that control biliary cholesterol secretion from the liver. 48 Our present study showed that MsrA expression promoted hepatic cholesterol efflux and excretion through the increase of ABCA1 and ABCG5/8 pathway, most probably due to the upregulation of LXRα.…”

Section: Discussionmentioning

confidence: 99%

Methionine sulfoxide reductase A attenuates atherosclerosis via repairing dysfunctional HDL in scavenger receptor class B type I deficient mice

Zhao

et al. 2020

FASEB j.

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High‐density lipoprotein (HDL), a well‐known atheroprotective factor, can be converted to proatherogenic particles in chronic inflammation. HDL‐targeted therapeutic strategy for atherosclerotic cardiovascular disease (CVD) is currently under development. This study aims to assess the role of methionine sulfoxide reductase A (MsrA) in abnormal HDL and its related disorders in scavenger receptor class B type I deficient (SR‐BI−/−) mice. First, we demonstrated that MsrA overexpression attenuated ROS level and inflammation in HepG2 cells. For the in vivo study, SR‐BI−/− mice were intravenously injected with lentivirus to achieve hepatic MsrA overexpression. High‐level hepatic MsrA significantly reduced the plasma free cholesterol contents, improved HDL functional proteins apolipoprotein A‐I (apoAI), apoE, paraoxonase1 (PON1), and lecithin:cholesterol acyltransferase (LCAT), while decreased the pro‐inflammatory property of dysfunctional HDL, contributing to reduced atherosclerosis and hepatic steatosis in Western diet‐fed mice. Furthermore, the study revealed that hepatic MsrA altered the expression of several genes controlling HDL biogenesis, cholesterol esterification, cholesterol uptake mediated by low‐density lipoprotein receptor (LDLR) and biliary excretion, as well as suppressed nuclear factor κB (NF‐κB) signaling pathway, which largely relied on liver X receptor alpha (LXRα)‐upregulation. These results provide original evidence that MsrA may be a promising target for the therapy of dysfunctional HDL‐related CVD.

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“…Elevated expression of OPN has been linked to coronary atherosclerotic lesions (Giachelli et al, 1993;Matsui et al, 2003;Ohmori et al, 2003), type 2 diabetes (Takemoto et al, 2000;Yamaguchi et al, 2004), and diabetic nephropathy (Hsieh et al, 2006;Kelly, Wilkinson-Berka, Ricardo, Cox, & Gilbert, 2002;Nicholas et al, 2010;Tachibana et al, 2012). Liver X receptors (LXRs) are ligand-dependent nuclear receptors that participate in cholesterol homeostasis and inflammatory signaling (de Wit, Vanmol, Kamermans, Hendriks, & de Vries, 2017;Schulman, 2017;Waddington, Jury, & Pineda-Torra, 2015). LXRs activate transcription via the binding of ligands either after heterodimerization with the retinoid X receptor (RXR) or another nuclear receptor after being activated by its own ligand (Jakobsson, Treuter, Gustafsson, & Steffensen, 2012).…”

mentioning

confidence: 99%

Activation of liver X receptor suppresses osteopontin expression and ameliorates nephrolithiasis

Chen

Zhang

et al. 2019

Journal Cellular Physiology

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Nephrolithiasis is a common disease of the urinary system, of which idiopathic calcium oxalate (CaOx) kidney stones, in particular, are one of the special types. In the initial stages of CaOx kidney stone formation, Randall's plaques (RPs) develop. Liver X receptors (LXRs) inhibit oxidative stress and inﬂammatory in other diseases; nevertheless, the role of LXRs in nephrolithiasis has yet to be elucidated. In this study, the role of LXRs in the progression of RP formation was investigated. Microarray analysis revealed that LXR/RXR levels were significantly greater in low‐plaque tissues (<5%) than in high‐plaque tissues (>5%), confirming the link between LXR activation and RP formation. Correspondingly, expression levels of two LXR target genes, LXRα and LXRβ, were lower in high‐plaque tissues than in low‐plaque tissues. In vitro, LXR agonist alleviated calcium oxalate monohydrate‐induced cellular calcium deposits and apoptosis. LXR activation decreased reactive oxygen species production and gene expression of inflammatory mediators, including osteopontin that has recently been demonstrated to correlate with the development of RPs. Moreover, p38 MAPK and JNK signaling may mediate LXR‐regulated expression in HK‐2 cells. In an animal model, the deposition was reduced by activating LXR, and osteopontin expression was also inhibited. Our findings suggest a role for LXRs in the progression of idiopathic CaOx kidney stones; LXR agonists may have therapeutic potential for the treatment of nephrolithiasis.

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Liver X receptors link lipid metabolism and inflammation

Cited by 166 publications

References 117 publications

The gut microbiota metabolite indole alleviates liver inflammation in mice

The gut microbiota metabolite indole alleviates liver inflammation in mice

Methionine sulfoxide reductase A attenuates atherosclerosis via repairing dysfunctional HDL in scavenger receptor class B type I deficient mice

Activation of liver X receptor suppresses osteopontin expression and ameliorates nephrolithiasis

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