Mevalonate Pathway
Lipids Metabolism

7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD), 2017.

New aspects of vitamin D metabolism and action — addressing the skin as source and target, 2020 fulltext

7-Dehydrocholesterol reductase (DHCR7) is involved in the last step in cholesterol synthesis, which in the case of the skin competes with vitamin D production as each requires the substrate 7-dehydrocholesterol (7-DHC). Thus DHCR7 activity is relevant to vitamin D production as it controls the level of the substrate for vitamin D production, namely 7-DHC. When exposed to UVB radiation, the path to vitamin D in the skin is initiated with breaking of the B ring of 7-DHC to form previtamin D3, which undergoes isomerization to vitamin D3.

Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome, 2022

• Abstract: Fragile X Syndrome (FXS) is the most frequent form of inherited X-linked pathology,
  associated with an intellectual and developmental disability, and currently considered the first
  monogenic cause of autism spectrum disorder (ASD). Low levels of total cholesterol reported in the
  serum of FXS patients, and evidence that FMRP targets a subset of mRNAs encoding proteins of lipid
  synthesis and transport suggests that the cholesterol metabolism impairments could be involved
  in FXS. Thus, the aim of the presented work was to investigate the modulations of the cholesterol
  biosynthetic pathway and its end-products in a recently developed Fmr1-∆exon 8 rat model of FXS.
  Here, we show that this experimental model mimics what is found in FXS patients, exhibiting
  a lower serum cholesterol content, accompanied by a reduction in food intake and body weight
  compared to WT animals. Moreover, alterations of proteins committed to cholesterol synthesis and
  uptake have been observed in the amygdala, prefrontal cortex and nucleus accumbens. Interestingly,
  the end-products show a brain region-dependent modulation in Fmr1-∆exon 8 rats. Overall, our
  results demonstrate that the cholesterol biosynthetic pathway is altered in some brain regions of
  this preclinical model of FXS. This finding has relevance for future studies to delve deeper into the
  involvement of this metabolic process in FXS, and thus its possible role as a therapeutic target.

Il metabolismo del colesterolo nel cervello e' indipendente dalla dieta per via della barriera ematoencefalica. nella sindrome da x fragile e autismo c'e' accumulo di colesterolo nel cervello perche' manca una idrossilasi CYP46A1 che idrossila ed elimina il colesterolo dal cervello, e diminuisce la via del mevalonato come feedback. Di conseguenza aumentano le zone lipid rafts delle membrane, e si alterano le vie di segnalazione, tipo rhoA che sta nelle zone non-raft. Inoltre queste cellule avranno meno CoQ!

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

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.