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, 115 (5), 1343-51

Sources of Fatty Acids Stored in Liver and Secreted via Lipoproteins in Patients With Nonalcoholic Fatty Liver Disease

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Sources of Fatty Acids Stored in Liver and Secreted via Lipoproteins in Patients With Nonalcoholic Fatty Liver Disease

Kerry L Donnelly et al. J Clin Invest.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage. The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD. Patients (5 male and 4 female; 44 +/- 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG. Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry. NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia. Of the TAG accounted for in liver, 59.0% +/- 9.9% of TAG arose from NEFAs; 26.1% +/- 6.7%, from DNL; and 14.9% +/- 7.0%, from the diet. The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD.

Figures

Figure 1
Figure 1
Model of lipid flux through the liver. Boxed numbers indicate the metabolic pathways traced using stable (nonradioactive) isotopes. DNL indicates new fat synthesis from 2-carbon precursors (e.g., dietary carbohydrate); chylomicrons are lipoproteins made in the intestine that carry dietary fat. FA, cellular fatty acids (fatty acids not esterified to glycerol but bound to a carrier protein); LPL, lipoprotein lipase.
Figure 2
Figure 2
Fatty acid sources in the fasted and fed states. (A and B) Sources of serum NEFA (A) and sources of tTRL TAG (filled symbols in B) were analyzed in the fasted and fed states. Sources of VLDL TAG (open symbols in B) were analyzed in the fasted state only. Data for fasting measurements were collected at 0645; fed-state concentrations were obtained 3 hours after lunch (1500) on each day. All data are mean ± SE; n = 9. (C) Insert shows the source contribution to tTRL TAG in the acute postprandial period. Patients consumed a meal consisting of whole foods at 0700; blood samples were obtained at 15-minute intervals until 0800, at 30-minute intervals until 0900, and then hourly until 1200.
Figure 3
Figure 3
Comparison of sources of TAG fatty acids in liver and lipoprotein fractions. (A and B) Sources of palmitate in VLDL, tTRL, and liver TAG accounted for after 5 days of labeling in subjects 1–9 (A), and the correlation between the percentage of TAG accounted for in the liver and VLDL (B). For both VLDL and tTRL, fasted-state values represent the average source contribution on day 5 at 0700 in subjects 1–9. Source contributions to tTRL TAG in the fed state were determined using the average values obtained on day 4 at 1500 in subjects 1–9. For comparison of liver TAG and VLDL TAG, fatty acid sources were normalized to 100%. Subject 3 has been omitted from this analysis due to undetectable concentrations of TAG in liver.

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