Caution on the Interpretation of Plasma Fatty Acid Composition as a Proxy Marker for SCD1 Activity: Particular Implications for Using the 16:1/16:0 Ratio in QTL Studies Involving Hyperlipidemic Patients
To the Editor:
Recently, Aldons Lusis and coworkers suggested a relationship between stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) activity and familial combined hyperlipidemia (FCH).1 The relationship between SCD1 and metabolic features related to FCH has attracted interest because it was shown that the SCD1 knockout mouse is obesity-resistant on high-fat feeding and has increased insulin sensitivity.2
The surrogate marker used for SCD1 activity is often the ratio of the product and precursor for the SCD1 enzymatic step, ie, either the ratio between 16:1n-7 and 16:0 or that of 18:1n-9 and 18:0 in plasma samples. Not only is this ratio very much dependent on previous food intake, it is also influenced by the fraction of lipids in plasma in which it is analyzed.3 The main plasma lipid fractions containing fatty acids are triglycerides, phospholipids, cholesteryl esters, and nonesterified fatty acids. Phospholipids, which have typical plasma concentrations of 2 to 3 mmol/L, show clear signs of fatty acid partitioning. They are enriched in long-chain polyunsaturated fatty acids, mainly 18:2n-6, but are relatively poor in, for example, 16:1n-7.3 Compared with plasma triglycerides, the plasma phospholipids are also poor in 18:1n-9 and rich in 18:0.3 Typical molar % of 16:1n-7 and 16:0 in plasma phospholipids are 2 and 30, whereas the average values for plasma triglycerides are 5% and 30%.3 The corresponding values for 18:1n-9 and 18:0 in plasma triglycerides are 28% and 4.5%, respectively, whereas the relative values are 10% and 14% for phospholipids. Importantly, the abundance of plasma phospholipids does not increase in proportion to triglycerides in the transition from normo- to hypertriglyceridemia.4,5⇓ The whole plasma fatty acid composition will therefore be dominated by the phospholipid fatty acids in plasmas with low triglycerides, whereas with increasing triglyceride concentrations the pattern will change toward reflecting the triglyceride fatty acids. Based on the known average differences in fatty acid of the major lipid fractions in plasma,3 the presumed net effect will provide an expected positive relationship between SCD1 desaturation index (16:1n-7 to 16:0 and 18:1n-9 to 18:0) and triglycerides, which actually has been demonstrated.6 Accordingly, assessment of the surrogate marker for SCD1 activity in whole plasma may generate data that are very difficult to interpret when groups with different triglyceride concentrations are compared, and, in fact, differences between such groups may not reflect SCD1 activity at all. This artifact can be circumvented by analyzing the fatty acid composition in one or more of the specific lipid fractions in plasma. Although not explicitly stated, it appears that Lusis et al1 have analyzed whole plasma fatty acid composition, and we believe this could have influenced their main findings. One of the strongest phenotypes of FCH is raised triglyceride concentrations. If the SCD1 desaturation indices are compared between FCH probands and non-FCH carriers, who by default have lower plasma triglycerides, the desaturation index will largely reflect the triglyceride concentration and to a lesser extent actual SCD1 activity. It is therefore unsurprising that linkage is observed with the HNF4α gene, which previously has been associated with triglyceride concentrations, both in FCH7 and in patients with maturity onset diabetes of the young.8,9⇓ We believe the linkage between SCD1 desaturation index and the several genes involving triglyceride metabolism would be different if the SCD1 desaturation index had been analyzed in defined lipid fractions. We also suggest that caution should be taken in future studies of SCD1 and its relationship to metabolic phenotypes; if the desaturation index (16:1n-7/16:0 or 18:1n-9/18:0) is to be used, it should be done in defined lipid fractions, and not in whole plasma.
- ↵Mar-Heyming R, Miyazaki M, Weisglas-Volkov D, Kolaitis N, Sadaat N, Plaisier C, Pajukanta P, Cantor RM, de Bruin TW, Ntambi JM, Lusis AJ. Association of stearoyl-CoA Desaturase 1 activity with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2008; 28: 1193–1199.
- ↵Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A. 2002; 99: 11482–11486.
- ↵Hodson L, Skeaff CM, Fielding BA. Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res. In press.
- ↵Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, Lusis AJ, Stalenhoef AF, Stoehr JP, Hayden MR, Ntambi JM. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J Lipid Res. 2002; 43: 1899–1907.
- ↵Weissglas-Volkov D, Huertas-Vazquez A, Suviolahti E, Lee J, Plaisier C, Canizales-Quinteros S, Tusie-Luna T, Aguilar-Salinas C, Taskinen MR, Pajukanta P. Common hepatic nuclear factor-4alpha variants are associated with high serum lipid levels and the metabolic syndrome. Diabetes. 2006; 55: 1970–1977.
- ↵Shih DQ, Dansky HM, Fleisher M, Assmann G, Fajans SS, Stoffel M. Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. Diabetes. 2000; 49: 832–837.