Biochemical site of regulation of bile acid biosynthesis in the rat.

Influence of bile acids on the activity of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase. 2. Effect of cholic acid in lymph fistula rats.

HE MORBID EXISTENCE of cholesterol within the walls of arteries represents the present prime threat to the physical well being of the Western world. Other modifying factors notwithstanding. its presence is the sine qua non of atherosclerosis. Extensive evidence from clinical, epidemiologic. and experimental derivations links cholesterol with this major form of occlusive vascular disease. Arterial and body cholesterol has its origins in both exogenous and endogenous sources. Several studies have indicated however that the bulk of arterial cholesterol in the natural disease state is of endogenous origin.‘,’ Accordingly then, knowledge of the mechanism of cholesterol formation is of profound importance. The Nobel award efforts of Lynen and Bloch as well as the work of many others have detailed precisely the biochemical steps required for the formation of cholesterol. In all. approximately 26 steps are known to be required to complete the biosynthesis of cholesterol from its precursor. acetyl CoA3,“. 18 acetyl CoA-cholesterol t 9 CO,. The early chemical reactions are part of pathways common to other metabolic end products. The fourth step however, the enzymatic reduction of betahydroxy-beta-methyl glutaryl CoA (HMG CoA) to mevalonic acid, is an irreversible reaction’ that leads nearly exclusively to cholesterol. It is at this step that one seeks and finds the prime locus of metabolic control for the biosynthesis of cholesterol. Studies utilizing isotopic mevalonate have shown that it and the intermediates beyond it are not subject to the same acute physiologic influences as are the compounds prior to this step.6 ’ It is of more than morphologic interest to observe that different enzymatic steps are separately packaged within the cell.9 ” Some reactions seem to have representation in two cellular compartments.‘~“~” The primal molecule, acetyl CoA, is the start of the synthetic sequence. Its successive condensation with itself is carried out initially in the cellsap, but HMG CoA reductase is found nearly exclusively in the microsomes. 9.” Following IV 14C acetate, over 90”,, ot the recovered 14C cholesterol is separated with the microsomal fraction after differential ultracentrifugation.9 In fact, most cellular cholesterol is associated with the microsomes.‘4 However, ketone body formation, which is actually ;I

On the control of cholesterol synthesis

Purification and Properties of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase from Pseudomonas

1
The rate limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase, is found in the microsomal fraction of a liver homogenate. It is markedly inhibited in vitro by the cholesterol metabolites cholate, deoxycholate, chenodeoxycholate and their taurine conjugates only at unphysiologically high concentrations.

2
The inhibition by taurochenodoxycholate is non-competitive and only partially reversible. Therefore, the effect of bile salts in vitro is interpreted as a non-specific detergent effect.

3
Feeding of cholic acid in the diet prevents the diurnal rhythm of the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The activity decreases with increasing time of feeding of cholic acid.

4
The specific activity of the enzyme decreases with increasing age of the animal.

5
It is concluded that the effect of bile salts in vitro on this enzyme cannot account for their effect in vivo. Rather, it is suggested that in vivo bile salts interfere with the de novo-synthesis and/or the degradation of the enzyme.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1971.tb01207.x

Influence of Bile Acids on the Activity of Rat Liver 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase

Cholesterol ist das mengenm~U3ig bedeutendste Steroid der Tierwelt. Es kommt in allen tierischen Geweben vor: frei, als Ester ges~ittigter und unges~tttigter laugkettiger Fetts~iuren und als Schwefels~urehalbester. Cholesterol ist Bestandteil der lipophilen Phasen des K6rpers, n~tmlich der Zellmembranen und der Lipoproteine. Der tierische Organismus stellt aus Cholesterol Gallens~uren und Steroidhormone her, Stoffe, die lebenswichtige Funktionen erffillen. Im Zusammenhang mit krankhaften Erscheinungen im menschlichen K6rper rfickte Cholesterol ins Blickfeld der Forscher. Zun/ichst als ,,Substance feuillet6, lamelleuse, brillante . . .\" in Gallensteinen entdeckt [t], erweckte es andauernde Aufmerksamkeit, als man fand, dab Atherome der Arterienw~nde einen ungew6hnlich hohen Gehalt an Cholesterolestern besitzen [2]. Cholesterol wird, wie vor allem Untersuchungen in den Arbeitskreisen yon BLoc~I [3], LYNEIq [4], PoPjAK und CORNFORTH [53, FOLKERS [63, RUDNEY [73 und anderen (Lit. [83, S. 305) ergeben haben, aus Acetat bzw. Acetyl-CoA* fiber viele Zwischenstufen synthetisiert. In Acetyl-CoA aber mfinden die Abbauwege yon Fetten, Kohlenhydraten und einer Reihe yon Aminos~iuren. Cholesterol seinerseits kann fiber Zwischenstufen, deren Aufkl~rung wir BERGSTR6M [93 und einer Reihe weiterer Arbeitsgruppen (Lit. [8], S. 329; [40]) verdanken, zu Gallens~iuren abgebaut werden (Fig. t).

B. Hamprecht

Papers

Regulation der Cholesterol-Synthese