Review
The evolution of plasma cholesterol: Direct utility or a “spandrel” of hepatic lipid metabolism?

https://doi.org/10.1016/j.plipres.2008.11.002Get rights and content

Abstract

Fats provide a concentrated source of energy for multicellular organisms. The efficient transport of fats through aqueous biological environments raises issues concerning effective delivery to target tissues. Furthermore, the utilization of fatty acids presents a high risk of cytotoxicity. Improving the efficiency of fat transport while simultaneously minimizing the cytotoxic risk confers distinct selective advantages. In humans, most of the plasma cholesterol is associated with low-density lipoprotein (LDL), a metabolic by-product of very-low-density lipoprotein (VLDL), which originates in the liver. However, the functions of VLDL are not clear. This paper reviews the evidence that LDL arose as a by-product during the natural selection of VLDL. The latter, in turn, evolved as a means of improving the efficiency of diet-derived fatty acid storage and utilization, as well as neutralizing the potential cytotoxicity of fatty acids while conserving their advantages as a concentrated energy source. The evolutionary biology of lipid transport processes has provided a fascinating insight into how and why these VLDL functions emerged during animal evolution. As causes of historical origin must be separated from current utilities, our spandrel-LDL theory proposes that LDL is a spandrel of VLDL selection, which appeared non-adaptively and may later have become crucial for vertebrate fitness.

Section snippets

The biological function of LDL cholesterol

Despite early scepticism, cholesterol is now accepted almost universally as a major contributory factor in atherogenesis [1], [2], [3] and few health issues now provoke more popular discussion, particularly amongst the “chattering classes”, than the cardiovascular risks presented by elevated concentrations of plasma cholesterol. Popular hysteria fuelled by almost endless media coverage has created a modern-day atmosphere in which fear of cholesterol, i.e. cholesterophobia, has been surpassed

VLDL and de novo hepatic lipogenesis (DNHL)

In the absence of any real quantitative information, it was believed for many years that one major function of VLDL was to transport fat, synthesized de novo from carbohydrate in the liver, to adipose tissue for storage as TAG. Thus, in this text-book version, VLDL was considered to form part of the overall process by which excess dietary carbohydrate was converted into stored fat. More recently this view has been questioned [21], [22], [23] on the basis of measurements of DNHL in vivo, and of

Evolutionary approach and animal models

If LDL cholesterol is merely a by-product of VLDL metabolism, then factors which influence hepatic VLDL secretion will obviously contribute to steady-state plasma LDL concentrations. Over the past 30 years, the molecular and physiological aspects of hepatic VLDL production have been studied intensively [8], [9], [19], [30]. Despite this wealth of information, the precise biological functions of VLDL remain unclear. Defining a physiological role for VLDL goes beyond simply stating the obvious:

The spandrel-LDL theory

In 1979, the evolutionary biologists Richard Lewontin and Stephen J. Gould used the architectural term “spandrel” to illustrate the distinction between the evolution of a phenotypic characteristic which conferred a selective advantage by its direct utility and one which merely arose as a necessary by-product of this process [334]. Therefore, the term “spandrel” refers to the adaptive use of a function selected for another purpose. A spandrel may subsequently be co-opted for highly fruitful use

Acknowledgements

We would like to thank the following colleagues for help and advice during the preparation of this manuscript: Esther Lubzens, Nick Myant, Allan Sniderman, Keith Frayn, Fredrik Karpe, Dick van der Horst and Robert Ryan.

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