Mevalonate Pathway
Lipids Metabolism

Author: Gianpiero Pescarmona
Date: 10/03/2007

Description

Mevalonate pathway

The end points of mevalonate pathway are

  • tRNA isopentenylation (addition to the heterocyclic ring of purine bases)
  • farnesyl- and/or geranylgeranyl- proteins
  • dolichol
  • Coenzyme Q
  • cholesterol
    • Steroid hormones
      • glucocorticoid/mineralcorticoid
      • sex steroids
      • cardioactive steroid hormones
      • neurosteroids

The mevalonate pathway activity is correlated with other activities:

  • Pgp (MDR)

what are the feedback and feedforward mechanisms of this pathway?

one more cartoon

Details of the single metabolic steps are described elsewhere.

Mevalonate pathway details

tRNA isopentenylation

Lung Cancer. 2007 Mar;55(3):271-7. Epub 2006 Dec 4.
Ethnic differences in frequencies of gene polymorphisms in the MYCL1 region and modulation of lung cancer patients' survival. 2007
Spinola M, Falvella FS, Galvan A, Pignatiello C, Leoni VP, Pastorino U, Paroni R, Chen S, Skaug V, Haugen A, Dragani TA.

Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy.
Abstract
Linkage disequilibrium (LD) analysis to refine a region associated with lung cancer progression on chromosome 1p34 identified a 106 kb LD block that includes MYCL1, TRIT1 (tRNA isopentenyltransferase 1) and MFSD2 (major facilitator superfamily domain-containing 2). Case-only association study on SNPs mapping in TRIT1 and MFSD2 indicated that the rare Leu allele (frequency: 0.04) of the TRIT1 Phe202Leu variation predicts short survival as compared to the common Phe/Phe genotype (hazard ratio (HR)=1.7; 95% CI, 1.03-2.86; P=0.039) in 335 Italian lung adenocarcinoma samples. A replication study in an independent population of 246 Norwegian lung cancer patients confirmed the significant association of the Phe202Leu polymorphism with patients' survival, but the rare allele was associated with better survival rate (HR=0.5; 95% CI, 0.26-0.91; P=0.023). The rare allele of TRIT1 Phe202Leu SNP was approximately seven-fold more frequent in Asian than in Caucasian subjects and three additional SNPs in the TRIT1 and MFSD2 genes showed ethnic differences in allelic frequencies. These results suggest that polymorphisms in the MYCL1 LD region affect lung cancer survival but that the functional element(s) may show population-specific patterns.

Cholesterol synthesis steps

Cholesterol synthesis requires:

  • Farnesyl diphosphate (= 2 isoprenoid units)

1 isoprenoid units ( 2 NADPH + 3 ATP each )

  • 2 AcetylCoA + 2 NADPH --> mevalonate
  • mevalonate + 3 ATP --> isopentenyl pirophosphate + 3 ADP + 1 CO2

Cholesterol and bile acids synthesis

The HMG-CoA reductase (or HMGR) is the rate controlling enzyme of the mevalonate pathway, and it is inhibited by statins

Cofactor requirements differ according to the final product.

Requirements from farnesyl-PP to:

  • cholesterol
  • dolichol
  • Coenzyme Q
  • farnesyl- and/or geranylgeranyl- proteins

Deciphering peripheral nerve myelination by using Schwann cell expression profiling 2002

Kegg; Terpenoids backbone biosynthesis

Statin-associated neuromyotoxicity 2005

Drugs Today 2005, 41(4): 267
Statin-associated neuromyotoxicity
Baker, S.K., Tarnopolsky, M.A.

The sequelae of cardiovascular disease contribute significantly to morbidity and mortality in developed nations. As a class, the statins have been shown to measurably reduce the burden of atherosclerotic illness. However, muscle- and, more recently, nerve-related toxicity have emerged as potential complications leading to treatment withdrawal. Generally, the myopathic signs and symptoms of tenderness, myalgias, cramping and elevated serum creatine kinase (CK) activity are fully reversible after drug discontinuation. Growing evidence suggests that latent or previously minimal symptomatic muscle disease may predispose to the development of myopathy. Less information is available regarding the natural history of the sensorimotor neuropathy, but it appears to be less reversible if large fiber function is clinically manifest. Pathophysiologic clues regarding the potential causes of statin myopathy with or without neuropathy are discussed with particular attention paid to the implications of disrupted mevalonate metabolism. For example, secondary defects in isoprenoid biosynthesis are expected to impair the production of a variety of intermediaries such as dolichols, which are crucial for N-linked glycosylation; geranylgeranyl pyrophosphate, which is necessary for coenzyme Q10 and G-protein synthesis; farnesyl-pyrophosphate, which facilitates the endoproteolytic cleavage and maturation of prelamin A and modifies B-type lamins and G-proteins; and isopentenylpyrophosphate, which is involved in a nucleoside modification of selenocysteinyl-tRNA and thus indirectly related to the synthesis of all selenoproteins (estimated at 35). The nature of statin neuromyotoxicity remains unresolved; however, investigating the cellular corollaries of deranged isoprenoid metabolism may uncover clues that lead to a more complete understanding of the elusive pathophysiology.

Regulation by AMPK

vedi

Cell compartmentalization of cholesterol biosynthesis.

Cell compartmentalization of cholesterol biosynthesis. 1996
Ann N Y Acad Sci. 1996 Dec 27;804:142-64.

Thus, the results showing the presence of cholesterol synthetic enzymes in peroxisomes (see references 1, 4, 5, 6, 7, 8, 12, 13, 20, 21, 22, 24, 25, and 26), the reduced levels of cholesterol synthesis enzymes and cholesterol synthetic capacity of cells and tissues lacking peroxisomes, 26, 37, 39 and the low serum cholesterol levels in patients suffering from peroxisomal deficiency diseases40-43 demonstrate that peroxisomes are essential for normal cholesterol synthesis. A number of metabolic pathways require co-participation of enzymes located in both peroxisomes as well as enzymes found in other intracellular compartments. For example, the first steps of plasmalogen synthesis occur in the peroxisomes, while the terminal reactions are completed in the endoplasmic reticulum. Similarly, the oxidation of cholesterol to bile acids requires the participation of enzymes localized in the endoplasmic reticulum as well as peroxisomes. Little is known about the regulation of such pathways or about the shuttling of intermediates between compartments. The physiological importance of peroxisomal enzymes in the regulation of sterol metabolism remains to be clarified.

Regulation of cholesterol synthesis by nuclear factors SREBP'S

  • Macrophage cholesterol biosynthesis was then studied in cells from diabetic mice treated with insulin and in glucose-enriched macrophages incubated with insulin. Insulin treatment of diabetic mice significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 81%, 54%, and 31% respectively, compared to macrophages isolated from nontreated diabetic mice. Similarly, insulin incubation with glucose-enriched macrophages significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 84%, 42%, and 18%, respectively, compared to macrophages incubated with high glucose but without insulin. These effects were mediated by glucose and insulin ability to regulate the transcription factor SREBP-1. Whereas glucose upregulated SREBP-1 expression and maturation, insulin blocked SREBP1 cleavage,
    High glucose concentration increases macrophage cholesterol biosynthesis in diabetes through activation of the sterol regulatory element binding protein 1 (SREBP1): inhibitory effect of insulin. 2008

One more figure

Regulated expression of the SREBPs is complex in that the effects of sterols are different on the SREBP-1 gene versus the SREBP-2 gene.

a deeper insight

Papers Insulin HMG-CoA reductase

Promoter analysis of the murine squalene epoxidase gene. Identification of a 205 bp homing region regulated by both SREBP'S and NF-Y.

Squalene synthase: structure and regulation.
.
Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and of incorporation of acetate into cholesterol in homozygous hypercholesterolemic fibroblasts by ferritin-low density lipoprotein conjugates. 1978

PPAR gamma ligand troglitazone lowers cholesterol synthesis in HepG2 and Caco-2 cells via a reduced concentration of nuclear SREBP-2.

Involvement of retinoid X receptor alpha in coenzyme Q metabolism.

Effects of granulocyte-macrophage colony-stimulating factor on the levels of VLDL and LDL receptor mRNAs in vivo.

Metabolism and function of coenzyme Q.

Cholesterol efflux

Macrophages

Serum Cholesterol sources
Liver (Pgp) induction by rifampicin (RFP), dexamethasone (DEX) and St. John's Wort

Infertility and coenzyme Q

Regulation of macrophage cholesterol efflux through hydroxymethylglutaryl-CoA reductase inhibition: a role for RhoA in ABCA1-mediated cholesterol efflux. 2005

cholesterol synthesis in diabetes

Prenylation inhibitors: a novel class of antiviral agents.

Highly unsaturated fatty acids suppress lipogenic gene transcription by reducing the DNA binding activity of several transcription factors

  • sterol regulatory-element binding protein 1 (HUFA inhibit the proteolytic release of sterol regulatory-element binding protein 1 from its membrane-anchored precursor through a ceramide-dependent signal)
  • nuclear factor Y (HUFA impart a post-translational modification to nuclear factor Y)

The multi-dimensional regulation of gene expression by fatty acids: polyunsaturated fats as nutrient sensors.

Inhibitors of mevalonate pathway

  • inhibitors of HMG CoA reductase (the statins)
  • of mevalonic acid-pyrophosphate decarboxylase (sodium phenylacetate and sodium phenylbutyrate)
  • farnesyl protein transferase (R115777, SCH66336, BMS-214662, Tipifarnib, L-778,123, and, prematurely, perillyl alcohol)

are dimmed by dose-limiting toxicities.
ref(this, 'jour', 'Exp Biol Med (Maywood).'

Sirolimus modifies cholesterol homeostasis in hepatic cells: a potential molecular mechanism for sirolimus-associated dyslipidemia.

Hyperphosphorylation regulates the activity of SREBP1 during mitosis.

Vascular endothelial growth factor activation of sterol regulatory element binding protein: a potential role in angiogenesis. 2004

Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells: a novel role of SREBP in regulating cholesterol metabolism.

Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses 2005

Control of gene expression by fatty acids. 2004

The mevalonate pathway during acute tubular injury: selected determinants and consequences. 2000

Tipo 2, niacina migliora attività dell'HDL
Nei pazienti con diabete mellito di tipo 2 e sindrome metabolica, l'impiego di niacina oltre che incrementare i livelli plasmatici di colesterolo Hdl sembrerebbe in grado di recuperare la perdita delle proprietà vasoprotettive di questa importante classe di lipoproteine. La conferma arriva da un gruppo di ricerca di Zurigo che, in uno studio pubblicato su Circulation, ha messo in evidenza i principali vantaggi offerti da terapie a rilascio prolungato di niacina in questi pazienti. In particolare, dopo aver isolato, da 10 individui sani e 33 diabetici, la frazione plasmatica contenente colesterolo Hdl, gli autori ne hanno misurato l'effetto sulla produzione di ossido nitrico e superossido mediante analisi spettroscopiche. In aggiunta, queste misurazioni sono state condotte nei pazienti dopo trattamento per tre mesi con niacina (1.500 mg/giorno) oppure con placebo. In breve, la somministrazione di niacina è risultata in grado di ristorare nei diabetici la capacità del colesterolo Hdl, osservata negli individui sani, di stimolare la produzione di ossido nitrico, di ridurre quella di superossido e di promuovere la riparazione di danni endoteliali (L.A.).
Circulation 2009, published online before print December 21

Ethanol

Human liver alcohol dehydrogenases catalyze the oxidation of the intermediary alcohols of the shunt pathway of mevalonate metabolism. 1991
Biochem Biophys Res Commun. 1991 Jan 31;174(2):701-7.
Keung WM.

Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, Massachusetts.
Abstract
Human liver alcohol dehydrogenase (ADH) catalyzes the oxidation of 3,3-dimethylallyl alcohol, the intermediary alcohol of the shunt pathway of mevalonate metabolism. ADH isozymes differ in their activities toward this alcohol in the order gamma 1 gamma 1 greater than gamma 2 gamma 2 approximately alfa alfa greater pi pi approximately beta 2 beta 2 approximately beta 1 beta 1 much greater than chi chi; kcat/Km values are 1.4 × 10(8), 1.9 × 10(7), 1.4 × 10(7), 5.6 × 10(6), 3.6 × 10(6), 1.6 × 10(6) and 2.5 × 10(3) M-1 min-1, respectively. The intermediary alcohols geraniol and farnesol of the proposed branch pathways of mevalonate metabolism are also oxidized by these isozymes with similar relative efficiencies. The genetic determinants of ADH isozymes may contribute to the observed differences in serum cholesterol levels among and within various populations.

P53

P53 Barsotti A

P53 mevalonate

Novel aspects of mevalonate pathway inhibitors as antitumor AGENTS, 2012

Comments
2010-03-26T15:07:26 - Paolo Pescarmona

The beginning

  • cholesterol
  • dolichol
  • Coenzyme Q
  • farnesyl- and/or geranylgeranyl- proteins

PUFA regulate metabolism

Fulltext

Extracellular Farnesol

!!

Heme stimulates cholesterol esterification in yeast

Stimulation by heme of steryl ester synthase and aerobic sterol exclusion in the yeast Saccharomyces cerevisiae. 1992 Arch Biochem Biophys. 1992 Aug 1;296(2):474-81.

  • Saccharomyces cerevisiae sterol and heme auxotrophs were used to elucidate a role for hemes in sterol esterification. Steryl ester synthase (SES) activity was stimulated on average fourfold in cells supplemented with 50 micrograms/ml delta-aminolevulinic acid (ALA). This stimulation was not dependent on ALA per se, but on the ability of this precursor to effect heme competency. The addition of ALA stimulated SES activity of yeast on either fermentative or respiratory carbon sources. The elevation of SES activity was independent of intracellular free sterol, unsaturated fatty acid, or methionine levels. SES activity increases as the cells enter stationary phase, and this increase is enhanced by heme competency. SES was directly inhibited by the hypocholesterolemic drug lovastatin (mevinolin). The inhibition of SES activity by lovastatin was enhanced in heme-competent cells.

B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells. 2007

Endocrinology. 2007 Aug;148(8):3722-9. Epub 2007 May 3.
"B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells. 2007"
Liang F, Kapoun AM, Lam A, Damm DL, Quan D, O'Connell M, Protter AA.
Source
Scios Inc., 6500 Paseo Padre Parkway, Fremont, California 94555, USA.
Abstract
In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis , cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Delta-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3beta-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2) . Consistent with the microarray and real-time PCR results, BNP also blocked Ang II-induced binding of (125)I-labeled low-density lipoprotein and (125)I-labeled high-density lipoprotein to human adrenocortical cells. Furthermore, BNP markedly inhibited Ang II-stimulated release of estradiol, aldosterone, and cortisol from cultured primary human adrenocortical cells. These findings demonstrate that BNP opposes Ang II-induced steroidogenesis via multiple steps from cholesterol supply and transfer to the final formation of steroid hormones. This study provides new insights into the cellular mechanisms by which BNP modulates Ang II-induced steroidogenesis in the adrenal gland.

Complete blockage of the mevalonate pathway results in male gametophyte lethality, 2009 PDF

2010-01-26T23:21:03 - Gianpiero Pescarmona

Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells. 1997

Lovastatin efficiently inhibited [3H]thymidine uptake promoted by all mitogens tested (76-87%); however, it significantly inhibited upregulation of c-fos mRNA levels induced only by insulin (33-67%, P < 0.05) and IGF-I (31 57%, P < 0.05). This inhibition was overcome by mevalonate and geranylgeraniol, and partially by farnesol. c-fos mRNA expression induced by 4-beta-phorbol-12-myristate-13-acetate, an activator of protein kinase C, was insensitive to lovastatin treatment

Biochem Pharmacol. 2004 Jan 15;67(2):303-13.
Statins upregulate CD36 expression in human monocytes, an effect strengthened when combined with PPAR-gamma ligands Putative contribution of Rho GTPases in statin-induced CD36 expression.

Ruiz-Velasco N, Domínguez A, Vega MA.

Servicio de Bioquímica-Investigación, Consejo Superior de Investigaciones Científicas, Hospital Ramón y Cajal, Ctra. Colmenar Viejo km. 9.1, 28034, Madrid, Spain.
Abstract

Scavenger receptor CD36 plays important roles in atherosclerosis, inflammation, thrombosis, and angiogenesis. Statins besides lowering serum cholesterol levels, exhibit a variety of effects on inflammation, coagulation and atherosclerosis lesion stability. PPAR-gamma ligands influence macrophage responses to many inflammatory stimuli. Herein, we investigated in human monocytes the effect of statins alone, and in combination with PPAR-gamma ligands on CD36 expression, as well as the molecular mechanisms underlying the regulatory action of statins. Our results demonstrate that statins upregulate both CD36 surface protein and mRNA by potentiating the transcription of the CD36 gene. Furthermore, the combination of statins and PPAR-gamma ligands has an additive effect on CD36 expression. Effects of statins on CD36 expression were prevented by mevalonate and geranylgeraniol, indicating the requirement of geranylgeranylated proteins for CD36 regulation. Rho GTPases inhibitor C3 exoenzyme reproduced the effect of statins, while Rho activator lysophosphatidic acid downregulated CD36. Transient expression of dominant-negative mutants of RhoA and RhoB induced a significant increased in CD36 promoter activity. Finally, the actin cytoskeleton disrupter cytochalasin D upregulated CD36. These data indicate that Rho proteins are important modulators of CD36 expression, and strongly suggest that statins increased CD36 expression by disrupting cytoskeleton organization by inactivating Rho GTPases. These features prompt to investigate the roles of Rho GTPases and actin cytoskeleton modulators on monocytic functions affected by statins.

Statins reduces

• isopenthenylPP
• dim
• farnesylPP
• geranylgeranylPP

The effects of statins are prevented by

• mevalonate (all)
• Farnesol (Ras dependent)
• Geranylgeraniol,

geranylgeranylated proteins are responsible for

CD36 regulation.

Int J Endocrinol. 2010;2010:957174. Epub 2009 Jul 21.
“Simvastatin does not affect vitamin d status, but low vitamin d levels are associated with dyslipidemia: results from a randomised, controlled trial.”: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=20016680

Rejnmark L, Vestergaard P, Heickendorff L, Mosekilde L.

Department of Endocrinology and Metabolism C, Aarhus Sygehus, Aarhus University Hospital, 8000 Aarhus, Denmark.
Abstract

Objectives. Statin drugs act as inhibitors of the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase enzyme early in the mevalonate pathway, thereby reducing the endogenous cholesterol synthesis. In recent studies, it has been suggested from epidemiological data that statins also may improve vitamin D status, as measured by increased plasma 25-hydroxyvitamin D (25OHD) levels. We now report the results from a randomised controlled trial on effects of simvastatin on plasma 25OHD levels. Design and Methods. We randomised 82 healthy postmenopausal women to one year of treatment with either simvastatin 40 mg/d or placebo and performed measurement at baseline and after 26 and 52 weeks of treatment. The study was completed by 77 subjects. Results. Compared with placebo, plasma levels of cholesterol and low-density lipoproteins decreased in response to treatment with simvastatin, but our study showed no effect of simvastatin on vitamin D status. However, plasma levels of triglycerides were inversely associated with tertiles of plasma 25OHD levels and changes in plasma triglycerides levels correlated inversely with seasonal changes in vitamin D status. Conclusion. Our data do not support a pharmacological effect of statins on vitamin D status, but do suggest that vitamin D may influence plasma lipid profile and thus be of importance to cardiovascular health.

J Pharmacol Sci. 2008 May;107(1):80-9. Epub 2008 May 9.
Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes.: http://www.ncbi.nlm.nih.gov/pubmed/18469500

Takaguri A, Satoh K, Itagaki M, Tokumitsu Y, Ichihara K.

Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Japan.
Abstract

A number of patients with hyperlipidemia are prescribed 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that are concomitantly used along with the treatment of diabetes mellitus. The effects of atorvastatin and pravastatin on insulin-induced glucose uptake and the related signal transduction in 3T3L1 adipocytes were studied. 3T3L1 fibroblasts were differentiated into adipocytes, pretreated with atorvastatin or pravastatin, and then exposed to insulin. Glucose uptake and the amount of insulin signal proteins were measured. Atorvastatin significantly decreased insulin-stimulated 2-deoxyglucose uptake in 3T3L1 adipocytes associated with the prevention of translocation of GLUT4 into the plasma membrane. The amounts of Rab4 and RhoA that required lipid modification with farnesyl or geranylgeranyl pyrophosphate, in the membrane fraction were decreased by atorvastatin. Insulin-induced tyrosine phosphorylation of IRS-1 and serine/threonine phosphorylation of Akt were reduced by atorvastatin. Pravastatin did not modify these insulin-induced changes in the signal transduction. Inhibitors of the RhoA/Rho kinase system, C3 and Y27632, as well as atorvastatin reduced insulin-induced changes in signal transduction. Atorvastatin and pravastatin did not affect messenger RNA expression, protein level, and tyrosine phosphorylation of insulin receptors. In conclusion, hydrophobic atorvastatin decreases the glucose uptake by 3T3L1 adipocytes since it can enter the cell and prevents lipid modification of some proteins that are involved in the insulin signal transduction process.

J Steroid Biochem Mol Biol. 2010 Mar 17. [Epub ahead of print]
The effects of 1,25-dihydroxyvitamin D(3) on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling.

Ordóñez-Morán P, Alvarez-Díaz S, Valle N, Larriba MJ, Bonilla F, Muñoz A.

Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain.
Abstract

Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH)(2)D(3) increases cytosolic Ca(2+) concentration and transiently activates RhoA and its effector the Rho-associated coiled-kinase (ROCK), and later p38MAPK-MSK. We found that the inhibition of ROCK signaling by Y27632 or that of MSK by Ro318220 prevent the formation of epithelioid islands of SW480-ADH cells by 1,25(OH)(2)D(3) and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH)(2)D(3) 24-hydroxylase (CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH)(2)D(3). Moreover, 1,25(OH)(2)D(3) does not promote the localization of the tight junction protein occludin at the plasma membrane in cells expressing a dominant negative RhoA (N19-RhoA). In addition, 1,25(OH)(2)D(3) specifically increases the level of the cysteine protease-inhibitor cystatin D, whereas that of cystatin SN is unaffected. The increase of cystatin D protein caused by 1,25(OH)(2)D(3) is abrogated in N19-RhoA cells. Thus, activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH)(2)D(3) in colon cancer cells.

J Steroid Biochem Mol Biol. 2010 Mar 17. [Epub ahead of print]
The effects of 1,25-dihydroxyvitamin D(3) on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling. : http://www.ncbi.nlm.nih.gov/pubmed/20223287

Ordóñez-Morán P, Alvarez-Díaz S, Valle N, Larriba MJ, Bonilla F, Muñoz A.

Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain.
Abstract

Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH)(2)D(3) increases cytosolic Ca(2+) concentration and transiently activates RhoA and its effector the Rho-associated coiled-kinase (ROCK), and later p38MAPK-MSK. We found that the inhibition of ROCK signaling by Y27632 or that of MSK by Ro318220 prevent the formation of epithelioid islands of SW480-ADH cells by 1,25(OH)(2)D(3) and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH)(2)D(3) 24-hydroxylase (CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH)(2)D(3). Moreover, 1,25(OH)(2)D(3) does not promote the localization of the tight junction protein occludin at the plasma membrane in cells expressing a dominant negative RhoA (N19-RhoA). In addition, 1,25(OH)(2)D(3) specifically increases the level of the cysteine protease-inhibitor cystatin D, whereas that of cystatin SN is unaffected. The increase of cystatin D protein caused by 1,25(OH)(2)D(3) is abrogated in N19-RhoA cells. Thus, activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH)(2)D(3) in colon cancer cells.

Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):144-50.
Signaling by the high-affinity HDL receptor scavenger receptor B type I. 2010

Saddar S, Mineo C, Shaul PW.

Division of Pulmonary and Vascular Biology, the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Scavenger receptor B type I (SR-BI) plays an important role in mediating cholesterol exchange between cells, high-density lipoprotein (HDL) cholesterol, and other lipoproteins. SR-BI in hepatocytes is essential for reverse cholesterol transport and biliary secretion of HDL cholesterol; thus, it is atheroprotective. More recently, it has been discovered that the HDL-SR-BI tandem serves other functions that also likely contribute to HDL-related cardiovascular protection. A number of the latter mechanisms, particularly in endothelial cells, involve unique direct signal initiation by SR-BI that leads to the activation of diverse kinase cascades. SR-BI signaling occurs in response to plasma membrane cholesterol flux. It requires the C-terminal PDZ-interacting domain of the receptor, which mediates direct interaction with the adaptor molecule PDZK1; and the C-terminal transmembrane domain, which directly binds membrane cholesterol. In endothelium, direct SR-BI signaling in response to HDL results in enhanced production of the antiatherogenic molecule nitric oxide; in a nitric oxide-independent manner, it serves to maintain endothelial monolayer integrity. The role of SR-BI signaling in the numerous other cellular targets of HDL, including hepatocytes, macrophages, and platelets, and the basis by which SR-BI senses plasma membrane cholesterol movement to modify cell behavior are unknown. Further understanding of signaling by SR-BI will optimize the capacity to harness the mechanisms of action of HDL-SR-BI for cardiovascular benefit.

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