Statiini vaikuttaa SIP signalointia, kun kalvomembraani joutuu muutokseen kolesterolin vähentyessä

http://www.ncbi.nlm.nih.gov/pubmed/23885725

Crit Rev Clin Lab Sci. 2013 May-Jun;50(3):79-89. doi: 10.3109/10408363.2013.813013.

Activation of sphingosine-1-phosphate signalling as a potential underlying mechanism of the pleiotropic effects of statin therapy.

Egom EE¹, Rose RA, Neyses L, Soran H, Cleland JG, Mamas MA.

Author information

Abstract

The mechanisms by which statins are beneficial are incompletely understood. While the lowering of low-density lipoprotein concentration is associated with regression of atherosclerosis, the observed benefit of statin therapy begins within months after its initiation, making regression an unlikely cause. Although LDL-C lowering is the main mechanism by which statin therapy reduces cardiovascular events, evidence suggests that at least some of the beneficial actions of statins may be mediated by their pleiotropic effects. Thus, statins may modulate the function of cardiovascular cells and key signalling proteins, including small G-proteins, to ultimately exert their pleiotropic effects. Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive lysophospholipid that regulates diverse physiological functions in a variety of different organ systems. Within the cardiovascular system, S1P mediates cardioprotection following ischemia/reperfusion injury, anti-inflammatory response, improvement of endothelial function, increased mobilization and differentiation of endothelial progenitor cells, inhibition of oxidation, and anti-atherogenic and anti-thrombotic actions. Early evidence suggests that the pleiotropic effects of statins may be related to an increase in S1P signalling. This review focuses on S1P signalling as the potential mechanism underlying the pleiotropic effects of statins. An improved understanding of this mechanism may be vital for establishing the clinical relevance of statins and their importance in the treatment and prevention of coronary artery disease. Key points Several studies have demonstrated a benefit from lowering serum LDL-C with statins in patients with and without clinical evidence of CAD. These may be mediated by the pleiotropic effects of statins-the mechanisms of which are incompletely understood. Early evidence suggests that statins may increase S1P signalling pathways through upregulation of the expression of S1P receptors and an increase in plasma levels of S1P to ultimately exert their pleiotropic effects. Future clinical trials and basic science research aimed at the underlying mechanisms of the pleiotropic effects of statins should enlighten us to their relative clinical relevance and importance.

PMID:

23885725

[PubMed - indexed for MEDLINE] 

Kommenttini. 

Sfingomyeliinin  kataboliasta muodostuu S1P ja joskus luin että D-vitamiini säätelee Sfingomyeliinin kataboliaa. kun Statiini vaikuttaa vähentynyttä kolesterolia  saattanee    D-vitamiinia  esiintyä liikkuvampana ja aktivoimassa SiP tietä- tosin  kolesterolilla ei kai ole mitään salvage jräjestelmää edes  plasmakalvorakenteessa kuten taas on  esim sfingomyeleiinillä- ja niin vnahentunut kolesteroli vain irtoaa ja vapauttaa  rasvaliukoista vitamiinia jota kerroksessa on., kun uutta kolesterolia ei  setukaan kerrokseen yhtä paljon kuin ennen  statiininv aikutuksesta- mikä tilanne siten pitää SiP ktabolisen tien  aktivoituna.  sillä kalvolipidienkin kesken vallitsee terve hierarkia.  SM ei yksinään lisäänny jos ei muita kalvofosfolipidikomponentteja ja kolesterolia myös  vastaavasti lisäänny.  

Sfingomyeliinin synteesipuolella vaadiittavat  vitamiinit olivat K-vitamiini ja B6.

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Kantaako riittoisa kolesterolikerros D-vitamiinin funktion paremmin?

http://www.ncbi.nlm.nih.gov/pubmed/25838999
Ehkä statiininkäyttäjien D-vitamiinintarve on normaalia suurempi.

N Am J Med Sci. 2015 Mar;7(3):86-93. doi: 10.4103/1947-2714.153919.

Statin Intolerance Because of Myalgia, Myositis, Myopathy, or Myonecrosis Can in Most Cases be Safely Resolved by Vitamin D Supplementation.Khayznikov M¹, Hemachrandra K¹, Pandit R¹, Kumar A¹, Wang P¹, Glueck CJ¹.Abstract

BACKGROUND: Low serum vitamin D can cause myalgia, myositis, myopathy, and myonecrosis. Statin-induced myalgia is a major and common cause of statin intolerance. Low serum vitamin D and statins, additively or synergistically, cause myalgia, myositis, myopathy, and/or myonecrosis. Statin-induced myalgia in vitamin D deficient patients can often be resolved by vitamin D supplementation, normalizing serum vitamin D levels.

AIMS: In 74 men and 72 women (age 59 ± 14 years) intolerant to 2 or more statins because of myalgia, myositis, myopathy, or myonecrosis and found to have ( under 32 ng/mL) serum vitamin D, we prospectively assessed whether vitamin D supplementation (vitamin D2: 50,000-100,000 units/week) to normalize serum vitamin D would allow successful rechallenge therapy with statins.

MATERIALS AND METHODS: Follow-up evaluation on vitamin D supplementation was done on 134 patients at 6 months (median 5.3), 103 patients at 12 months (median 12.2), and 82 patients at 24 months (median 24).

RESULTS: Median entry serum vitamin D (22 ng/mL, 23 ng/mL, and 23 ng/mL) rose at 6 months, 12 months, and 24 months follow-up to 53 ng/mL, 53 ng/mL, and 55 ng/mL, respectively  on vitamin D therapy (50,000-100,000 units/week). On vitamin D supplementation, serum vitamin D normalized at 6 months, 12 months, and 24 months follow-up in 90%, 86%, and 91% of the patients, respectively.

 On rechallenge with statins while on vitamin D supplementation, median low-density lipoprotein cholesterol (LDLC) fell from the study entry (167 mg/dL, 164 mg/dL, and 158 mg/dL) to 90 mg/dL, 91 mg/dL, and 84 mg/dL, respectively. On follow-up at median 6 months, 12 months, and 24 months on statins and vitamin D, 88%, 91%, and 95% of the previously statin-intolerant patients, respectively, were free of myalgia, myositis, myopathy, and/or myonecrosis.

CONCLUSIONS: Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis associated with low serum vitamin D can be safely resolved by vitamin D supplementation (50,000-100,000 units /week) in most cases (88-95%).

KEYWORDS: Myalgia; myonecrosis; myopathy; myositis; rhabdomyolysis; statin intolerance; statin rechallenge; vitamin D deficiency; vitamin D supplementation

PMID: 25838999 [PubMed]  PMCID: PMC4382771  Free PMC Article

Kolesterolin historiasta

 Isäni KJ Uotin oppikirja Rudolf Franck: Moderne Ernährungstherapie  (Berlin, Vogel, 1933), mainitsee sivulla 27  kolesterolia  (cholesterin) käsittelevässä kappaleessa  seuraavan ajatuksen:
" ihmisessä oleva kolesteroli on exogeenista, vain ravinnosta tulevaa".

"Der Körper vermag wahrscheinlich selbst kein Cholesterin aufzubauen, da "der tierische Körper der Ringbildung nicht fähig ist"( ABDERHALDEN ). Als Quelle des Cholesterins kommt daher nur unsere Nahrung ( Eier, Hirn, Milch- in Pflanzen, Samen und Keimlingen die Phytostearine) in Betracht ".

Mutta - jatkaa Rudolf Franck:
 "Nach BEUMER, LEHMANN und  SCHÖNHEIMER  ist es  doch wahrscheinlich, dass Cholesterin im tierischen Körper aus einfachen Bausteinen aufgebaut werden kann." 

Tähän Rudolf Frank jatkaa :
"Ähnliches gibt auch für Menschen, jedoch vermag  der Körper das Cholesterin nicht wieder abzubauen. Die Haut ist eine der Stätten, wo der Körper seine Lipoide  deponiert. Dem  Cholesterin haftet immer etwas Ergosterin an, das durch Ultraviolettbestrahlung aktiviert wird und einen starken Einfluss auf den Kalkstoffwechsel ausübt.

(Kaikenkaikkiaan kolesteroli on molekyyli, jonka aineenvaihdunnalla on pitkä ja mielenkiintoinen historiaeikä  sen tulevaisuuttakaan ole vielä kirjoitettu)

6.4. 2016

NNR 2012 Kolesterolin ravintosuositukset

NNR 2012 kertoo KOLESTEROLISTA  omana kappaleenaa sivulla 225-226. 

Nyt tiedetään, että kehossa voi monet solut valmistaa kolesterolia ja sitä tuotetaan sappihappojen muodostusta varten sekä steroidihormonien rakentamiseen ja solukalvon struktuuriin.  Kolesterolinsynteesi on hyvin tarkasti säätynyt kehossa.  Jos solut ottavat sisäänsä (exogeenista)  kolesterolia, silloin endogeeninen kolesterolinsynteesi alenee.  Joka päivä ihmiskehossa syntetisoituu  1 gramma kolesterolia. Sehän merkitsee 3- 4 kertaa suurempaa määrää, mitä Pohjoismaisesta dieetistä päivittäin imeytyy kehoon. 

Kolesterolin tärkeimmät ravintolähteet ovat liha, sisälmysravinto, munat ja maitotuotteet. 

 Fraktionaalinen kolesterolin imeytyminen alenee, jos saanti lisääntyy. Keskimäärin imeytyy dietäärisestä kolesterolista 30 - 40 %.  Mutta yksilöitten kesken imeytymiselläkin on eroja.  Imeytyminen vaihtelee 20- 80 prosentin väliä. 

On tehty kontrolloituja sokkokokeita  1974- 1999 ja näistä ( 17 tutkimuksesta)   on tehty meta-analyysi.

Jos ravinnossa on 100 mg kolesterolia, nousee seerumin kolesteroli 0.056 mmol/L ja HDL-kolesteroli 0.008 mmol/L   ja vaikuttaa   totaali kolesteroli/HDL-kolesterolisuhteeseen hieman , 0.020 yksikön verran. 

Niillä yksilöillä, joilla on apoproteiini E4-alleeli, ravintoperäisellä kolesterolilla on suurempi vaikutus seerumin kolesterolipitoisuuteen.  Vastaavasti niillä, joilla ei ole apoproteiini E4alleelia dieetin kolesterolin vaikutus seerumin kolesteroliin on vähäisempi. 

Useat asiantuntijaryhmät, pääasiassa Amerikasta, ovat suositelleet kolesterolin oton rajoiksi  alle 300 mg kolesterolia päivässä ja niille, joilla on suuri riski sydänverisuonitaudeista, esim 2- tyypin -diabeetikoille suositellaan, ettei kolesterolin saanti ylitä 200 mg  päivittäistä   tasoa.  pohjoismaissa on kolesterolin  keskimääräinen saanti 250- 350 mg päivässä. Oletetaan, että  suositeltaessa sellaisia dietäärisiä linjauksia, joissa edistetään kasvisravinnon käyttöä ja rajoitetaan rasvaisten maito-ja lihatuotteiden käyttöä, samalla  vaikutetaan kolesterolin saannin alenemista. Tämän takia ei nykyisissä suosituksissa NNR 2012 aseteta mitään ylärajaa kolesterolin saannille. Ilmeiseti endogeeninen kyky syntetisoida koleterolia riittää jopa  ennenaikaisesti tyntyneen vauvan tarpeisiin.  Sentatkia ei ole mitään suosituksisa siitäkään, että vauvojen syöttökaavioon pitäisi sisällyttää kolesterolia, vaikka kolesteroli on rintamaidon luonnollinen komponentti. 

Päivitys 6.4. 2016
Kommenttini: Minulle uusi asia on tuo  kolesterolisuosituksen rajan lasku  200 mg /pv tasoon riskipotilaille. olen aika varovainen tässä suosituksessa, sillä  miten  paljon  endogeeni kolesterolituotanto pääsee  jylläämään, jos exogeeni vaimentaja kovasti lasketaan. Tietysti  saattaa kolesterolinkaltiasilla kasvismolekyyleilläkin olla sitä vaimennusefektiä, mutta  sitä ei tässä tarkemmin mainita. Kuitenkin kananmunan keltuaisella on muitakin positiivisia  piirteitä xantofylliinit ja luteiini, joten  sitä ei ainakaan kokonaan kannata  eliminoida kolesterolilähteitä vähennettäessä. Eikös se yksi kananmuna  antaisi n 300 mg  kolesterolia. Niin olen ainakin aiemmin oppinut.  

Kolesterolin historiasta -synteesin selvittelystä Nobel 1964 Kondrad Bloch, Feodor Lynn

http://www.nutri-facts.org/eng/expert-opinion/detail/backPid/598/article/a-hundred-year-history-of-cholesterol/

A hundred year history of cholesterol

May 01, 2015 - 

Winners of the Nobel Prize in 1985, Professors Joseph Goldstein (seated) and Michael Brown (standing) of the University of Texas recently wrote a brief history of cholesterol and heart disease over the previous century in Cell – with a highly justified focus on their own groundbreaking research contribution.

Joseph Goldstein, MD; Michael Brown, MD; University of Texas, Dallas, USA

"Today, around 25% of all deaths in industrialized countries can be attributed to coronary heart disease. It may come as some surprise that heart attacks were first recognized as a clinical condition as late as 100 years ago. In 1910, the German chemist, Adolf Windaus found the first hint that cholesterol tended to mass in atherosclerotic plaques. In 1938, Norwegian physician Carl Müller first described the hereditary condition familial hypercholesterolemia (FH) where the concomitant greatly increased blood cholesterol levels were associated a massive increase in a risk of heart attack in middle age. In 1955, John Gorman, a physician from the University of California, first separated blood lipoproteins from blood plasma into LDL and HDL. He then looked at the plasma of patients who had had heart attacks and consistently found significantly higher levels of LDL and lower levels of HDL.

On a population level, communities with low fat intakes also tend to have low cholesterol levels in their blood, but if they should move from that community to a region with high fat intake, then their plasma cholesterol levels will rise to a similar level as the locals. 

Cholesterol is indirectly synthesized from repeated polymerization of the simple acetate moiety. In 1964, the Nobel Prize was given to Konrad Bloch and Feodor Lynen who first found the metabolite 3-hydroxy-3 methyl glutarate attached to CoA (HMG CoA) which was dedicated to cholesterol synthesis. From this discovery, research concentrated on regulating the cholesterol synthesis rate controlling enzyme, HMG CoA reductase.

A LDL particle is spherical in shape with a phospholipid coating around a core filled with cholesterol ester molecules. A single protein, apoliprotein B (apoB), is bound to the phospholipid surface. One theory as to the role of LDL in plaque formation is that it partially penetrates the vascular epithelium. The exposed lipids are oxidized, which in turn modify the ApoB structure. The modified ApoB attracts the attention of wandering macrophages in the blood, which ingest the LDL and are then themselves converted to cholesterol-laden foam cells. The foam cells themselves secrete metabolites that result in severe local inflammation and the initiation of plaque formation.

In the late seventies, Goldstein and Brown were able to demonstrate how cells take up LDL. They found specific surface receptors in cells (clustered in coated pits) that bind with the apoB. The LDL is then admitted to the cell where cholesterol is released by the action of cholesterol esters. They also discovered a homeostatic feedback mechanism that meant increased cell cholesterol levels resulted in a reduction in the production of LDL receptors and the HMG CoA reductase. There is an important genetic component to density of LDL receptors in cells. The genes of sufferers of familial hypercholesterolemia (FH) result in a major reduction in the concentration of LDL receptors, hence the cells are much less able to process cholesterol with a resulting massive build-up of cholesterol in the blood plasma itself.

It was in 1976 that the Japanese company Sankyo first developed the class of cholesterol lowering pharmaceutical agents known as statins. They work by inhibiting the cellular production of HMG CoA reductase. However, it was not until 1987, that the first statin for human use was approved (Merck’s Mevacor). Whilst it was known that statin regulated the cells cholesterol feedback mechanism, it was not known how. This situation was resolved by Goldstein and Brown in the nineties. They found a key regulating substance called sterol regulatory element binding protein-1 (SBREP-1) and over the following years, elucidated its complex intracellular journey from the cell membrane to the nucleus. 

The targeted application of therapies design to reduce LDL levels in blood has undoubtedly made a major contribution in treating and preventing heart disease. However, the decision on when to intervene remains complex and would be aided immeasurably if rapid, non-invasive methods could be developed that detect and monitor atherosclerotic plaques in the coronary arteries."

Based on: Goldstein JL & Brown MS, A Century of Cholesterol and Coronaries: From Plaques to Genes and Statins, Cell 161, March 26, 2015

Last updated: 01.05.2015