Gerald F. Holland

Chapter 19. Disorders of Lipid Metabolism

Publisher Summary This chapter discusses advancement in the area of metabolism of plasma lipoproteins and their role in the atherogenic process, the cellular basis of familial hypercholesterolemia, and the clinical effects and mechanisms of action of clofibrate. Lipoprotein base (LL) has been implicated in a newly proposed mechanism, which attributes key roles, not only to low density lipoproteins (LDL), but also to very low-density lipoprotein (VLDL) and chylomicrons. LL presence in the arterial wall suggests that the concentration of LDL at the blood-artery interface may greatly exceed concentrations in circulating blood. The clinical prominence of clofibrate as a hypolipidemic agent has provided the impetus for numerous studies of its mechanism of action. Clofibrate and structurally related agents prevents fatty livers produced by orotic acid. Several reports describing the effects of tibric acid in plasma lipid levels in man and animals have appeared. This structurally distinct agent is the most potent member from a series of sulfamylbenzoic acids and owes its hypolipidemic effect to a reduction in the hepatic level of α-glycerophosphate, an essential triglyceride precursor. RMI 14,514 inhibits hepatic biosynthesis of fatty acids, and reduces plasma cholesterol and triglyceride levels in rats. The mechanism of action of RMI 14,514 on hepatic lipogenesis appears to be distinct from that of cIofibrate.

Chapter 18. Disorders of Lipid Metabolism

Publisher Summary This chapter discusses the recent advances in disorders of lipid metabolism. Two new hypotheses on plaque development have been proposed. Once plaque formation has been initiated, the lesion may remain fixed, regress or become a nidus for deposited cholesterol. An increase of 100 mg percent in serum cholesterol gave a 50% increase in intimal plasma lipoproteins (LP)-bound cholesterol, but did not appear to increase the unbound cholesterol. The finding that in normal aortic intima there is intact LP which appears to be in equilibrium with plasma LP has prompted to suggest that the arterial LP cholesterol pool should be more accessible to metabolic and exchange processes than the unbound cholesterol pool. The perifibrous lipid in normal intima, the pool of amorphous atheroma lipid under raised plaques and the lipid within fat-filled cells in fatty streaks are no longer in the form of intact LP in equilibrium with plasma LP, but represent unbound cholesterol. Evidence in man suggests that cholesterol enters the plasma in the free form and is esterified within the plasma by the action of lecithin:cholesterol acyl transferase (LCAT) for which the preferred substrates are high density lipoprotein (HDL) cholesterol and lecithin. LCAT indirectly reduces the unesterified cholesterol and lecithin of plasma LP other than HDL, by virtue of the non-enzymatic equilibration of these lipids among other LP.

Selected Papers on Drug Effects

In previous reports [153, 155, 156, 158] we described the properties of a group of chemically nonrelated substances, such as Phenylbutazone, Chloropromazine, local anesthetics, etc. to prevent blood cell aggregation of the type that may lead to thrombosis, namely red cell and platelet aggregation. These properties were present both in vivo and in vitro and seemed to be mediated by some type of membrane action [158]. They were termed “Anti-Adhesive Drugs”.

Studies with 5-(3-Pyridyl)Tetrazole, a Long-Acting Lipolysis Inhibitor

Although the hypocholesteremic effect of nicotinic acid was reported by Altschul et al1. in 1955, general agreement as to its mechanism of action has not been reached. The demonstration that nicotinic acid is a potent lipolysis inhibitor2, capable of markedly reducing the level of plasma free fatty acids (FFA)3, offers a basis for an explanation of its hypocholesteremic effect.