▪ Abstract Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the over...

/pdf/pleiotropic-effects-of-statins-1b9b1g8457.pdf

Pleiotropic effects of statins

The molecular mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E-containing lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands additional amounts that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.

https://science.sciencemag.org/content/sci/294/5545/1354.full.pdf

CNS synaptogenesis promoted by glia-derived cholesterol

Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.

https://www.pnas.org/content/pnas/77/7/3957.full.pdf

Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)31357-5.pdf

Interpretation of the evidence for the efficacy and safety of statin therapy.

Statins (HMG-CoA reductase inhibitors) are used widely for the treatment of hypercholesterolemia. They inhibit HMG-CoA reductase competitively, reduce LDL levels more than other cholesterol-lowering drugs, and lower triglyceride levels in hypertriglyceridemic patients. Statins are well tolerated and have an excellent safety record. Clinical trials in patients with and without coronary heart disease and with and without high cholesterol have demonstrated consistently that statins reduce the relative risk of major coronary events by approximately 30% and produce a greater absolute benefit in patients with higher baseline risk. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis, and inflammation. Mechanisms independent of LDL lowering may play an important role in the clinical benefits conferred by these drugs and may ultimately broaden their indication from lipid-lowering to antiatherogenic agents.

Current Perspectives on Statins

https://www.jstage.jst.go.jp/article/antibiotics1968/29/12/29_12_1346/_pdf

Ml-236a, ml-236b, and ml-236c, new inhibitors of cholesterogenesis produced by penicillium citrinum

CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species.

1 ML-236A and ML-236B, potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, were readily absorbed into the liver, the major site of cholesterogenesis, after oral administration in mice; peak concentration of these inhibitors in the liver, which were attained within 60 min after administration, were 4% of the dose for ML-236A and 10% for ML-236B, respectively



2 ML-236B reduced sterol synthesis from both [14C]acetate and [14C]octanoate in rat liver slices to 50% of control at a concentration of 005 μg/ml (012 μM) but not that from [14C]mevalonate at higher concentrations up to 125 μg/ml Inhibition of sterol synthesis was also observed in liver slices obtained from rats which had previously received this compound



3 ML-236B was also inhibitory in vivo to cholesterol synthesis in various tissues of rats in which [14C]acetate was intraperitoneally injected to the animals and labeled digitonin-precipitable sterols synthesized were isolated and determined Sterol synthesis in the liver was far more strongly inhibited (over 90 % at 4h after oral administration of 50 mg/kg of ML-236B) than that in other organs tested including kidney, lung, adrenal, spleen, and testis



4 These findings strongly suggest that hypocholesterolemic activity of ML-236A and ML-236B is owing largely to specific inhibition of hepatic cholesterol synthesis

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1977.tb11637.x

Inhibition of Cholesterol Synthesis in vitro and in vivo by ML-236A and ML-236B, Competitive Inhibitors of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2880%2981223-3

Yoshio Tsujita

Papers

Ml-236a, ml-236b, and ml-236c, new inhibitors of cholesterogenesis produced by penicillium citrinum

CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species.

Inhibition of Cholesterol Synthesis in vitro and in vivo by ML-236A and ML-236B, Competitive Inhibitors of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase

WHHL-Rabbit: a low density lipoprotein receptor-deficient animal model for familial hypercholesterolemia

Tissue-selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor