Regulation of 3-hyfroxy-3-methyl glutaryl ICOA reductase by moradrenaline and adenosine compounds

Abstract

Extensive studies carried out in different laboratories have brought to light several effectors which influence the hepatic biogenesis of cholesterol and the activity of HMG CoA reductase. The delineation of the mechanism of regulation of HMG CoA reductase depends on understanding the nature of action of these effectors. The foregoing investigations were carried out in order to get an insight into some of the regulatory agents of HMG CoA reductase activity in rat liver. These studies have yielded interesting results regarding the mechanism of its regulation by noradrenaline and adenosine compounds. Autonomic nervous system in the regulation of HMG CoA reductase The autonomic nervous system apparently controls several metabolic processes by regulating the activities of several enzymes. The opposing influence of the sympathetic and parasympathetic nervous systems on enzymes like hepatic tyrosine aminotransferase (TAT) is well known. This effect is considered to play an important role in the regulation of this enzyme in vivo. The stimulation by noradrenaline points out that in the case of HMG CoA reductase, the sympathetic nervous system is effective. The lack of any effect on the enzyme by the cholinergic agent (Chapter III) excludes the possibility of involvement of the cholinergic nervous system in its regulation. Though ATP, the purported purinergic transmitter substance, shows stimulatory effect on HMG CoA reductase, purinergic blocking agents do not abolish the effect (Chapter IV). Hence, it should be assumed that this response involves some other mechanism. Lack of involvement of the adrenergic receptors The effects of catecholamines are known to be mediated through the or adrenergic membrane receptors. These hormones combine with either or both of these receptors and bring about specific cellular responses. It is established that the adrenoceptor is associated with the adenyl cyclase system which on stimulation generates cyclic AMP, the “second messenger”. Blocking agents have been used to identify adrenoceptor mediated effects of noradrenaline. Results with adrenergic blocking agents (Chapter III) suggest that in stimulating HMG CoA reductase activity, noradrenaline does not depend on the membrane receptors. Noradrenaline as the effector molecule The question whether noradrenaline or a derived metabolite is the active compound is next considered. Agents such as Ro 4 1284, which enhance endogenous noradrenaline concentration, also stimulate the biogenesis of cholesterol, as expected. Pargyline, a potent inhibitor of monoamine oxidase which degrades noradrenaline, also stimulates cholesterol biogenesis. These findings support the view that noradrenaline itself is the effector which elicits the stimulatory effect on cholesterol biogenesis and HMG CoA reductase activity. But further study is required before such a conclusion can be drawn, especially considering the positive effects obtained with some catechol compounds at higher concentrations (Chapter III). Intracellular action of noradrenaline The evidences in favour of an intracellular action of noradrenaline in stimulating HMG CoA reductase are indirect. The lack of involvement of adrenergic membrane receptors is the first and foremost. The experiments with 3,4 dihydroxyphenylserine, which is known to give rise to noradrenaline in the cytosol on decarboxylation, also favour a mechanism involving intracellular action of noradrenaline. If this is further substantiated, it would place noradrenaline among the list of intracellularly acting hormones such as glucocorticoids and estradiol. Cellular action of steroid hormones An intracellular action of noradrenaline is reminiscent of the action of steroid hormones. Glucocorticoids, mineralocorticoids and estrogens have been shown to exert their action directly within the cell. Intensive investigations have shown that the primary event in steroid action is the highly specific binding of the hormone to certain allosteric receptor proteins within the cytosol. This differs from non steroidal hormones, most of which act at the cell membrane. The steroid receptor complex then interacts with chromosomal acceptor sites, facilitating protein synthesis which exerts physiological effects. The present study prompts similar parallel studies and a search for specific binding proteins for noradrenaline in the cytosol. Stimulatory effect observed with catechol compounds Analogues of steroids can bind to the cytosolic receptor but differ in biological activity due to structural differences. Many catechol compounds tested for their effect on HMG CoA reductase show stimulatory effects similar to noradrenaline. Hence, they may also bind to a proposed receptor whilst exerting their action. Noradrenaline, however, is active at far lower concentrations. Catecholamines and adenosine compounds-two classes of vasoactive agents Can adenosine compounds also share the same or similar cytosolic receptor in stimulating HMG CoA reductase Both classes of compounds are amines present in biological systems. However, catecholamines are vasoconstrictive, whereas adenosine compounds are vasodilative. A major difference is that adenosine compounds stimulate HMG CoA reductase only when the enzyme activity is depressed (e.g., starvation, cholesterol feeding), whereas noradrenaline is effective both in normal and starved rats. Dependence of circadian rhythm of HMG CoA reductase on food intake Starvation refeeding studies show that maximum sterol synthesis from acetate occurs about 6 hours after feeding. Rats being nocturnal eat predominantly during early dark hours. Hence, the rhythm of HMG CoA reductase is dependent on diet intake. The most remarkable depression of HMG CoA reductase is seen in starvation, which is reversed on refeeding. Calorie source of any kind is sufficient to maintain normal activity, indicating no special dietary inducer. A metabolite within the cell which rises with feeding may be responsible. ATP is a probable effector; other adenosine compounds also show this effect. Injected ATP or adenosine increases their liver concentration. How the rhythm persists even during starvation indicates additional factors or hormones are involved. Hormones implicated in the rhythm include insulin, glucagon, thyroid hormones, catecholamines and glucocorticoids. According to Rodwell, hormonal effects fall into: (i) positive control (insulin, thyroid hormone), (ii) permissive (thyroid hormone, insulin), (iii) negative control (hydrocortisone, glucagon). Modulation of the activity of HMG CoA reductase Early theories suggested allosteric regulation by cholesterol itself, but this has been disproven. Current evidence suggests modulation of catalytic efficiency is possible in addition to synthesis/degradation control. The ATP Mg–dependent inhibition of HMG CoA reductase is key. The absence of inhibition in repeatedly washed microsomes and solubilized enzyme indicates the presence of a membrane component involved in inactivation. Whether this involves phosphorylation or acylation is not yet known. Fatty acids or cholesterol esters were tested but did not account for inhibition. Hydroxylamine, a fatty acyl acceptor, did not reverse inhibition. Hence the nature of the inactivation reaction remains elusive.