Fat Fuels the Flame

Abstract

See related article, pages 381–390 Recent reviews duly recite the prevailing concept of the mechanisms of atherogenesis.1–5 According to this model, a surfeit of low-density lipoproteins (LDL) favors accumulation and retention of these particles in the arterial intima. There, LDL undergoes oxidative modification. Lipid mediators derived from this oxidized LDL stoke the inflammation now widely deemed a critical culprit in the formation and complication of atheroma.6 This oft repeated schema rests on a firm experimental foundation. Clinical and human pathological observations corroborate this view. Yet, the “oxidized LDL” hypothesis may not explain all aspects of atherogenesis. Most laboratory experiments with oxidized LDL use mixtures of products of incubation of LDL with transition metals. The Fenton chemistry used to generate oxidized LDL in the laboratory may have little to do with the oxidative processes at work in the atherosclerotic arterial wall. Biochemical studies have however begun to identify the structures of components oxidized LDL that do elicit proinflammatory effect on cells involved in atherogenesis.3,4 The lack of clinical benefit of antioxidant vitamin supplements does not alone vitiate a pathogenic role for oxidized LDL.7,8 Antioxidant vitamins may well not distribute to the proper compartments or may be chemically inappropriate agents for the oxidation chemistry that pertains to lipoproteins entwined with the intimal extracellular matrix during atherogenesis. The clinical trials of antioxidant vitamins may have enrolled patients at a stage of their disease too advanced to show a benefit of the antioxidant strategy. LDL lowering does consistently confer clinical benefit, even in trials in which antioxidants have failed …