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Journal of Lipid Research, Vol. 47, 2562-2574, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans

Aruna Vedala^*, Wei Wang^*, Richard A. Neese^*, Mark P. Christiansen^* and Marc K. Hellerstein^1,*,

^* Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA 94720
Division of Endocrinology and Metabolism, San Francisco General Hospital, University of California, San Francisco, CA 94110

Published, JLR Papers in Press, August 23, 2006.

¹ To whom correspondence should be addressed. e-mail: march{at}nature.berkeley.edu

ABSTRACT

Newly synthesized triglyceride (TG) may exit the liver immediately as VLDL-TG or be stored and secreted after a delay. We quantified the contributions from plasma NEFA, diet, and de novo lipogenesis (DNL) to VLDL-TG via immediate and delayed pathways in five lean, normolipidemic subjects; six obese, hypertriglyceridemic (HPTG) nondiabetics; and six obese, HPTG diabetics. Intravenous [²H₃₁]palmitate and [1-¹³C₁] acetate and oral [²H₃₅]stearate were administered for 30 h preceding an overnight fast. [1,2,3,4-¹³C₄]palmitate was infused during the subsequent 12 h fast. Contributions from plasma NEFA via the immediate pathway were 64 ± 15, 33 ± 6, and 58 ± 2% in control, HPTG, and diabetic HPTG, respectively. Delayed pool fractional contributions were as follows: dietary FA, 2.0 ± 0.9, 2.5 ± 1, and 12 ± 2%; DNL, 3 ± 0.3, 14 ± 3, and 13 ± 4%; delayed NEFA, 15 ± 4, 20 ± 4, and 30 ± 3%. VLDL-TG production rates and absolute input rates from the delayed pool were significantly higher in HPTG and diabetic HPTG than in controls. In conclusion, we provide direct kinetic evidence for a hepatic TG storage pool in humans and document its metabolic sources. The turnover time and sources of this pool differ in diabetic HPTG and nondiabetic HPTG, with potential therapeutic implications.

Supplementary key words hypertriglyceridemia • diabetes • obesity • hepatic cytosolic pool • stable isotopes • mass spectrometry • very low density lipoprotein • nonesterified fatty acid

Abbreviations: DNL, de novo lipogenesis; FAME, fatty acid methyl ester; GCRC, General Clinical Research Center; HPTG, hypertriglyceridemia, hypertriglyceridemic; MPE, molar percent excess; TG, triglyceride; TRL, triglyceride-rich lipoprotein

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