Mevalonate pathway
The end points of mevalonate pathway are
- cholesterol
- dolichol
- Coenzyme Q
- farnesyl- and/or geranylgeranyl- proteins
one more cartoon
Details of the single metabolic steps are described elsewhere.
Cholesterol synthesis steps
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
Regulation by AMPK
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Regulation of cholesterol synthesis by nuclear factors SREBP'S
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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.
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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.
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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