Cholesterol in health and disease

Imagine if an excess amount of a critical, life-sustaining molecule like ATP were, by a perverse series of events involving the lifestyle of modern humans, causally related to a major human disease. The thought of “ATP” being synonymous with poor health and poor living in the minds of the lay public and press, even of health care providers, would be difficult for any selfrespecting scientist to accept. So one might view the biomedical history of cholesterol — indeed, this history might be seen as even stranger than the hypothetical ATP scenario, given that evolution has devoted close to 100 genes to the synthesis, transport, metabolism, and regulation of cholesterol. This structurally fascinating lipid is utterly essential to the proper functioning of cells and organisms. Cholesterol, cholesterol metabolites, and immediate biosynthetic precursors of cholesterol play essential roles in cellular membrane physiology, dietary nutrient absorption, reproductive biology, stress responses, salt and water balance, and calcium metabolism. Indeed, many of the articles in this Perspective series are devoted to the normal physiology of cholesterol. Still, there is little doubt that the disease process responsible for the leading cause of death in the industrialized world — atherosclerosis — is a disorder in which an excess of cholesterol is a major culprit. How did evolution come up with a molecule that is critical for so many aspects of normal physiology, and what went “wrong”? The physiology of cholesterol Cholesterol and cellular membranes: an evolutionary perspective. As organisms became more complex, cells required membranes that would provide the proper conformational environment for a wide variety of integral membrane proteins, such as channels, transporters, and enzymes. Moreover, the cells of these advanced organisms required sophisticated signaling machinery, and this machinery would have to be organized as multiprotein complexes in focal, nonhomogenous areas of cellular membranes. Put simply, these requirements were met by focally increasing the “stiffness” or viscosity of phospholipid bilayers. In theory, this goal could be achieved by increasing the degree of saturation of the fatty acyl moieties of membrane phospholipids. However, unsaturated fatty acids in these phospholipids, particularly in the sn-2 position, are needed for a wide variety of cellular signaling functions, and so an exogenous “stiffening factor” was needed. This factor would have to be able to pack tightly with the long saturated and unsaturated fatty acyl chains of membrane phospholipids through van der Waals interactions. This would require a long, flat, and properly shaped hydrophobic molecule, accompanied by additional features (see below) to help further stabilize this interaction. To meet these needs, nature began with molecules, probably originating from prebiotic anaerobic times, that were formed by the sequential condensation of the two-carbon acetate molecule. Prokaryotes evolved enzymes to synthesize more complex linear molecules from these precursors (e.g., carotenoids), which were able to meet the membrane-organizing requirements of most of these primitive organisms. These primitive molecules, however, lacked the proper shape, rigidity, and amphipathic nature to properly organize the mem