LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor

Zelcer, Noam; Hong, Cynthia; Boyadjian, Rima; Tontonoz, Peter

doi:10.1126/science.1168974

Cited by 703 publications

(779 citation statements)

References 33 publications

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“…Protein extracts from cells or livers were obtained and analyzed as described previously (31). ABCA1 levels were determined using rabbit polyclonal anti-ABCA1 (Novus Biologicals, 1:1,000 dilution in TBS + 1% Tween 20) and normalized to α-tubulin (Santa Cruz Biotechnologies, 1:5,000 dilution in TBS + 1% Tween 20).…”

Section: Methodsmentioning

confidence: 99%

miR-33 links SREBP-2 induction to repression of sterol transporters

Marquart

Allen

Ory

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

505

501

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The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.

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Section: Methodsmentioning

confidence: 99%

miR-33 links SREBP-2 induction to repression of sterol transporters

Marquart

Allen

Ory

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

505

501

View full text Add to dashboard Cite

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“…Mechanistically, this atheroprotective effect has been attributed to enhanced reverse cholesterol transport and inhibition of inflammatory responses upon LXR activation [16,17]. Direct LXR target genes include those encoding the ATP-binding cassette (ABC) transporter A1 (ABCA1) and the ABC transporter G1 (ABCG1), which govern cholesterol efflux from macrophages and peripheral organs, and the inducible degrader of LDL receptor (Idol [also known as Mylip]), which decreases LDL receptor protein levels and peripheral cholesterol uptake [18,19]. In macrophages, LXR activation inhibits the expression of inflammatory cytokines (i.e.…”

Section: Introductionmentioning

confidence: 99%

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

et al. 2013

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Aims/hypothesis Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes.Methods Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β +/+ (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β −/− mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N ,N -dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Results Even in the absence of diabetes, Lxrα/β −/− mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β +/+ mice. When challenged with diabetes, Lxrα/β −/− mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. Conclusions/interpretation These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

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“…Liver X receptors (LXRs) are activated by oxidized cholesterol derivatives and belong to a family of nuclear receptors that form heterodimers with the retinoid X receptor to regulate transcription of target genes governing cholesterol, fatty acid, and glucose metabolism (16,17) (18). LXRs consist of two isoforms, LXRα, which is abundantly expressed in liver, small intestine, kidney, macrophages, and adipose tissue, and LXRβ, which is expressed more ubiquitously (19).…”

mentioning

confidence: 99%

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

135

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The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.soluble (pro)renin receptor | liver X receptor | aquaporin-2 | frizzled-8 | β-catenin F ull-length (Pro)renin receptor (PRR), a 350-amino acid transmembrane receptor for prorenin and renin, is subjected to protease-mediated cleavage to produce a 28-kDa protein of the N-terminal extracellular domain, the soluble (pro)renin receptor (sPRR), and the 8.9-kDa C-terminal intracellular domain called "M8.9" (1, 2). Before the cloning of full-length PRR in mesangial cells as an integral 39-kDa membrane protein (3), M8.9 was identified as a truncated protein associated with the vacuolar H + -ATPase (V-ATPase) from bovine chromatin granules (4). The cleavage occurs in Golgi apparatus through furin (5) or ADMA19 (6). An sPRR ELISA kit has been developed to detect sPRR in plasma and urine samples (7) . With this assay, increased serum sPRR levels have been demonstrated in patients with heart failure (8), kidney disease (9, 10), hypertension (11), and preeclampsia (2). Moreover, serum sPRR is positively associated with serum creatinine, blood urea nitrogen, and urine protein and is inversely associated with the estimated glomerular filtration rate in patients with chronic kidney disease caused by hypertension...

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LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor

Cited by 703 publications

References 33 publications

miR-33 links SREBP-2 induction to repression of sterol transporters

miR-33 links SREBP-2 induction to repression of sterol transporters

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

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