Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

Li, Hai; Chen, Wei; Zhou, Yue; Abidi, Parveen; Sharpe, Orr; Robinson, William H.; Kraemer, Fredric B.; Li, Jingwen

doi:10.1194/jlr.m800375-jlr200

Cited by 80 publications

(79 citation statements)

References 45 publications

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“…Our previous studies and others have demonstrated that BBR, a plant-derived hypolipidemic compound, increases LDLR expression through dual mechanisms of enhancing LDLR mRNA stability (30)(31)(32)(33) and blocking PCSK9 transcription ( 26,34 ). HNF1 ␣ protein levels were reduced in BBR-treated HepG2 cells, which accounted for, in part, the inhibitory action of BBR on PCSK9 expression.…”

Section: Discussionmentioning

confidence: 99%

Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters

Dong

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org effect of statins in dyslipidemic hamsters. J. Lipid Res . 2010. 51: 1486-1495. Supplementary key words LDL receptor • rosuvastatin • berberineThe number of LDL receptors (LDLR) expressed on the surface of hepatocytes is a primary determinant for plasma LDL-cholesterol (LDL-C) levels ( 1 ). Hepatic LDLR mediates the uptake of LDL particles from the circulation and delivers the receptor-bound LDL to the endosomal system for degradation while the LDLR returns to the cell surface. Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the cellular cholesterol biosynthetic pathway. The inhibition of cholesterol de novo synthesis leads to increased numbers of cell surface LDLR by activation of LDLR gene transcription. Thus, statins are the most widely prescribed drugs to treat hypercholesterolemia and combined hyperlipidemia.Contrary to human studies in which statins effectively lower plasma total cholesterol (TC) and LDL-C, in animal studies, the LDL reducing effects of statins exhibit great species differences. Statins reduce plasma TC and LDL-C as the major drug action in rabbits, miniature pigs, dogs, monkeys, and guinea pigs ( 2-4 ) but not in rodents such as rats and hamsters ( 5-7 ). In rats and hamsters fed either a Abstract We investigated the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the resistance of dyslipidemic hamsters to statin-induced LDL-cholesterol (LDL-C) reduction and the molecular mechanism by which statins modulated PCSK9 gene expression in vivo. We utilized the fructose diet-induced dyslipidemic hamsters as an in vivo model and rosuvastatin to examine its effects on liver PCSK9 and LDL receptor (LDLR) expression and serum lipid levels. We showed that rosuvastatin induced PCSK9 mRNA to a greater extent than LDLR mRNA in the hamster liver. The net result was that hepatic LDLR protein level was reduced. This correlated closely with an increase in serum LDL-C with statin treatment. More importantly, we demonstrated that in addition to an increase in sterol response element binding protein 2 (SREBP2) expression, rosuvastatin treatment increased the liver expression of hepatocyte nuclear factor 1 ␣ (HNF1 ␣ ), the newly identifi ed key transactivator for PCSK9 gene expression. Our study suggests that the inducing effect of rosuvastatin on HNF1 ␣ is likely a underlying mechanism accounting for the higher induction of PCSK9 than LDLR because of the utilization of two transactivators (HNF1 ␣ and SREBP2) in PCSK9 transcription versus one (SREBP2) in LDLR transcription. Thus, the net balance is in favor of PCSK9-induced degradation of LDLR in the hamster liver, abrogating the effect of rosuvastatin on LDL-C lowering. Press, January 4, 2010 DOI 10.1194 Abbreviations: BBR, berberine; HNF1, hepatocyte nuclear factor 1; LDL-C, LDL-cholesterol; LDLR, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SREBP, sterol response element binding protein; TC , total cholesterol; TG, triglyceri...

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Section: Discussionmentioning

confidence: 99%

Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters

Dong

et al. 2010

Journal of Lipid Research

Self Cite

218

155

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“…Electrophoretic Mobility Shift Assays-HepG2 nuclear extracts were prepared as described (19). A double-stranded oligonucleotide, designated as ACSL3-PPRE, was end-labeled with T4 polynucleotide kinase in the presence of [␥-32 P]ATP.…”

Section: Methodsmentioning

confidence: 99%

Long Chain Acyl-CoA Synthetase-3 Is a Molecular Target for Peroxisome Proliferator-activated Receptor δ in HepG2 Hepatoma Cells

Cao

Zhou

et al. 2010

Journal of Biological Chemistry

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ACSL3 is a member of the long chain acyl-CoA synthetase (ACSL) family that plays key roles in fatty acid metabolism in various tissues in an isozyme-specific manner. Our previous studies showed that ACSL3 was transcriptionally up-regulated by the cytokine oncostatin M (OSM) in HepG2 cells, accompanied by reduced cellular triglyceride content and enhanced ␤-oxidation. In this study, we investigated the molecular mechanism underlying the OSM-induced activation of ACSL3 gene transcription in HepG2 cells. We showed that OSM treatment resulted in a coordinated elevation of mRNA levels of ACSL3 and peroxisome proliferator-activated receptor ␦ (PPAR␦). The effect of OSM on ACSL3 mRNA expression was inhibited by cellular depletion of PPAR␦. By utilizing a PPAR␦ agonist, L165041, we demonstrated that activation of PPAR␦ led to increases in ACSL3 promoter activity, mRNA level, and protein level in HepG2 cells. Analysis of the ACSL3 promoter sequence identified two imperfect PPAR-responsive elements (PPRE) located in the ACSL3 promoter region ؊944 to ؊915, relative to the transcription start site. The up-regulation of ACSL3 promoter activity by PPAR␦ was abolished by deletion of this PPREcontaining region or mutation to disrupt the binding sites. Direct interactions of PPAR␦ with ACSL3-PPRE sequences were demonstrated by gel mobility shift and chromatin immunoprecipitation assays. Finally, we provided in vivo evidence showing that activation of PPAR␦ by L165041 in hamsters increased ACSL3 mRNA and protein levels in the liver. These new findings define ACSL3 as a novel molecular target of PPAR␦ in HepG2 cells and provide a regulatory mechanism for ACSL3 transcription in liver tissue. Perturbed fatty acid (FA)2 metabolism is one underlying contributor to the development of obesity, diabetes, and cardiovascular diseases. One family of enzymes that plays critical roles in FA metabolism is the long chain acyl-CoA synthetases (ACSL) (1, 2). ACSLs catalyze the formation of fatty acyl-CoAs from ATP, CoA, and long chain fatty acids. This reaction is the first step in lipid metabolism after FA entry into the cell and the activation process is necessary for FA cellular utilization in different metabolic pathways including the catabolic pathway for the degradation of FA via the ␤-oxidation system and the anabolic pathway for the synthesis of phospholipids, cholesterol esters, and triglycerides (TG).Since the initial report on ACSL1 in 1990 (3), major progress has been made in the identification and characterization of other members of the acyl-CoA synthetase family.

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“…From our previous in vitro studies, HNRNPD, along with two other LDLR ARE-BPs (HNRNPI and KSRP), were demonstrated to act as mRNA decaypromoting factors ( 21 ). Knocking down each of these proteins in HepG2 cells resulted in elevations of LDLR mRNA.…”

Section: In Vivo Knockdown Of Hnrnpd Elevated Liver Ldlr Expression Tmentioning

confidence: 99%

“…Some ARE-BPs are mRNA destabilizing inducers, while others can protect the mRNA from endonuclease cleavage (18)(19)(20). Our previous studies have identifi ed heterogeneous nuclear ribonucleoprotein (HNRNP)D, HNRNPI, and KH-type splicing regulatory protein (KSRP) as decay-promoting factors that bind to ARE sequences of LDLR 3 ′ UTR and accelerate the mRNA decay in HepG2 cells ( 21 ). A recent new study identifi ed human antigen R (HuR) as a stabilizing factor for LDLR mRNA ( 22 ).…”

Section: Measurement Of Serum Lipid Levelsmentioning

confidence: 99%

A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

Singh¹,

Kan²,

Shende³

et al. 2014

Journal of Lipid Research

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The expression of liver LDL receptor (LDLR) regulates human plasma LDL-cholesterol (LDL-C) homeostasis ( 1-3 ). Increased hepatic LDLR expression results in improved clearance of plasma LDL-C through receptor-mediated endocytosis, which is strongly associated with a decreased risk of developing cardiovascular disease in humans ( 4, 5 ). Thus far, many studies have demonstrated that intracellular cholesterol levels play a primary role in determination of hepatic LDLR expression levels through a negative feedback mechanism that controls gene transcription mediated by the sterolregulatory element (SRE) located in LDLR promoter and SRE binding proteins (SREBPs) ( 6, 7 ).In addition to transcriptional regulation, LDLR gene expression is subject to posttranscriptional regulation at the point of mRNA stability ( 8-11 ). It is well-known that mRNA stability plays a key role in the control of gene expression both by setting the basal level of gene expression and as a site of regulatory responses ( 12 ). In liver cells, when intracellular cholesterol levels rise, LDLR mRNA levels fall substantially along with transcripts of other SREBP target genes ( 13 ). While this decrease in LDLR mRNA abundance has been attributed to the transcriptional suppression due to the inhibition of proteolytic processing of SREBP ( 14, 15 ), it is currently unknown whether elevated cholesterol levels can also elicit a cellular response to increase LDLR mRNA turnover rate as a rapid means to

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Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

Cited by 80 publications

References 45 publications

Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters

Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters

Long Chain Acyl-CoA Synthetase-3 Is a Molecular Target for Peroxisome Proliferator-activated Receptor δ in HepG2 Hepatoma Cells

A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

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