Biologia

Review article
Mechanisms of Disease

The Human Plasma Lipidome
Oswald Quehenberger, Ph.D., and Edward A. Dennis, Ph.D.

From the Departments of Medicine and Pharmacology (O.Q.) and the Departments of Chemistry and Biochemistry and Pharmacology (E.A.D.), School of Medicine, University of California, San Diego, La Jolla. Address reprint requests to Dr. Dennis at the University of California,San Diego, School of Medicine, Department of Pharmacology, 9500 Gilman Dr., La Jolla, CA 92093-0601, or at edennis@ucsd.edu. N Engl J Med 2011;365:1812-23.
Copyright © 2011 Massachusetts Medical Society.

holesterol and triglyceride levels are now assessed routinely, and physicians regularly prescribe lipid-lowering drugs to patients found to have dyslipidemia. However, the increase in thenumber of patients with metabolic diseases (including type 2 diabetes and obesity, which are associated with an elevated risk of cardiovascular disease) demands more detailed lipid analyses both for diagnostic purposes and for monitoring the efficacy of prescribed therapy. Human plasma comprises nucleic acids, amino acids (mostly in the form of proteins), carbohydrates (in the form of monosaccharidesand disaccharides), and lipids (Fig. 1).1-3 Much is known about the first three constituents, but among the various cellular metabolites, lipids stand out because of their structural diversity and the sheer number of discrete molecular species — in the hundreds of thousands, according to some estimates4 (Fig. 2). The lipids in plasma are solubilized and dispersed through their association withspecific groups of proteins. Most free fatty acids and related structures with carboxyl functional groups associate with albumin, whereas the transport and distribution of more complex lipids are accomplished by means of plasma lipoproteins.5 The structural diversity of lipids is mirrored by the enormous variation in their physiological function. The abundance of individual lipid molecular speciesin plasma may be indicative of the variety of specific human diseases. In this review, we discuss the application of metabolic-profiling strategies to quantitatively measure entire lipid categories in human plasma, and we examine the potential use of the diverse lipid metabolites as diagnostic tools or therapeutic targets.

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Di v er si t y of L ipids in Hum a n Pl a sm a
In view of theimportance of lipids to biologic and pathophysiological processes, detailed knowledge of the composition and concentration of lipid metabolites in plasma would be expected to expand our diagnostic capabilities. To this end, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in collaboration with the National Institute of Standards and Technology (NIST), recently issued aplasma-based standard reference material (SRM 1950 Metabolites in Human Plasma) for the purpose of metabolite analysis (www.nist.gov). Historically, wide-scale lipid profiling has been difficult to perform because the diverse physical properties of lipid metabolites require a multitude of purification systems combined with a host of complex technical procedures. The evolution of lipidomics has driventhe development of new analytic platforms, specifically in the area of mass spectrometry, which have streamlined these procedures and have allowed many more lipid molecules to be analyzed in great detail. A high-resolution lipidomic
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n engl j med 365;19

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MECHANISMS OF DISEASE

Fatty acyls

Nucleic acids Amino acids Lipids Sterol lipids

Glycerolipids

Prenol lipids

Glycerophospholipids Carbohydrates (sugars)

Sphingolipids

Figure 1. Relative Distribution of Biologic Molecules in Human Plasma. Amino acids and nucleic acids...