Contributions from plasma NEFA, diet and de novo lipogenesis-derived fatty acids to fasting VLDL-triglycerides via the delayed secretory pathway in humans

doi:10.1194/jlr.M600200-JLR200

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Contributions from plasma NEFA, diet and de novo lipogenesis-derived fatty acids to fasting VLDL-triglycerides via the delayed secretory pathway in humans

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

Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720-3104

Corresponding Author: march{at}nature.berkeley.edu

Newly synthesized hepatic triglyceride (TG) may exit the liver as VLDL-TG immediately or be stored in the cytosol and secreted after a delay. We quantified in humans the contribution from plasma NEFA, diet and de novo lipogenesis (DNL)-derived fatty acids (FA) to fasting VLDL-TG via the immediate and delayed secretory pathways by a stable isotope labeling approach. Five lean, normolipidemic subjects; six obese, hypertriglyceridemic non-diabetic (HPTG) subjects; and six obese, diabetic HPTG subjects were studied. Intravenous [2H31]-palmitate and [1-13C1]- acetate and oral [2H35]-stearate were administered during the 30 hour period preceding an overnight fast. [1,2,3,4-13C4]-palmitate was infused intravenously during the subsequent 12 hr overnight fasting period. The contributions from plasma NEFA via the immediate secretory pathway were 64±15%, 33±6% and 58±2% in control, HPTG and diabetic HPTG groups, respectively. Dietary FA contributed 2.0±0.9%, 2.5±1% and 12±2%, while DNL provided 3±0.3%, 14±3% and 13±4%, in the three groups. The summed delayed pathway contribution from all measured sources was 20±3%, 36±7% and 56±5% in the three groups, leaving unaccounted (unlabeled) contributions of 25±13%, 32±11% and <0%. VLDL-TG production rates and the absolute input rate from the delayed pool were significantly higher in both HPTG and diabetic HPTG than controls. In conclusion, we provide kinetic evidence for an hepatic TG storage pool in humans and document its sources and its importance in HPTG. The turnover time of this pool is shorter and the metabolic sources of TG differ in diabetic HPTG than in non-diabetic HPTG, however. These differences may have therapeutic implications.

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				E. J. Parks, L. E. Skokan, M. T. Timlin, and C. S. Dingfelder Dietary Sugars Stimulate Fatty Acid Synthesis in Adults J. Nutr., June 1, 2008; 138(6): 1039 - 1046. [Abstract] [Full Text] [PDF]

				M. F-F Chong, L. Hodson, A. S Bickerton, R. Roberts, M. Neville, F. Karpe, K. N Frayn, and B. A Fielding Parallel activation of de novo lipogenesis and stearoyl-CoA desaturase activity after 3 d of high-carbohydrate feeding Am. J. Clinical Nutrition, April 1, 2008; 87(4): 817 - 823. [Abstract] [Full Text] [PDF]

				M. K. Hellerstein Exploiting Complexity and the Robustness of Network Architecture for Drug Discovery J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 1 - 9. [Abstract] [Full Text] [PDF]

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