The evolution of plasma cholesterol: direct utility or a "spandrel" of hepatic lipid metabolism?

Prog Lipid Res. 2009 Mar;48(2):73-91. doi: 10.1016/j.plipres.2008.11.002. Epub 2008 Nov 21.


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.

Publication types

  • Review

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Biological Evolution
  • Cholesterol / blood*
  • Cholesterol, LDL / physiology
  • Cholesterol, VLDL / physiology
  • Fatty Acids / metabolism
  • Humans
  • Lipid Metabolism / genetics
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Models, Animal
  • Selection, Genetic


  • Cholesterol, LDL
  • Cholesterol, VLDL
  • Fatty Acids
  • Cholesterol