Sources of fatty acids in hepatic and lipoprotein triacylglycerol: Studies in transgenic mice, and in humans with nonalcoholic fatty liver disease

To investigate the flux of lipid to and from the liver in hypertriglyceridemic mice, and in humans with nonalcoholic fatty liver disease (NAFLD), stable isotopes were used to trace three potential sources of fatty acids stored in the liver and secreted in the blood: serum nonesterified fatty acids (NEFA), dietary fatty acids, and newly-made fatty acids from the de novo lipogenesis (DNL) pathway. Txnip-/- mice were fed an isotopically-labeled chow diet for 15 d to trace de novo cholesterol synthesis and DNL (1-13C1 acetic acid) and liver triacylglycerol (TAG) derived from dietary fatty acids (glyceryl tri(hexandecanoate-d 31). Txnip-/- mice had significantly elevated (P < 0.05) serum NEFA concentrations compared to wild type (WT) littermates, their livers weighed more and contained more TAG and total cholesterol. Liver CE content was elevated despite lower cholesterol fractional synthesis rates (16% d-1 vs. 31% d-1 in Txnip-/- and WT, respectively). Lipogenesis was significantly greater in Txnip-/- (1.47 +/- 0.08 vs. 0.49 +/- 0.06 mumol/d). To quantitate the sources of hepatic- and serum lipoprotein-TAG in NAFLD, nine patients scheduled for a medically-indicated liver biopsy were infused and fed stable isotopes for 4 d. NAFLD patients were obese with fasting hypertriglyceridemia (3.3 +/- 2.2 mmol/L) and hyperinsulinemia (114 +/- 78 pmol/L). Of the TAG accounted for in liver, 59.0 +/- 9.9% of TAG arose from NEFA, 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 study, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. The data presented in this dissertation support elevated DNL as the primary contributor to liver TAG in Txnip-/-, although increased esterification of fatty acids also contributed to excess liver TAG and CE. Similarly, elevated lipogenesis made a significant contribution to liver fat in NAFLD. In addition to providing strong evidence for targeting lipogenesis as a therapeutic approach for this condition, these quantitative metabolic data document the contribution of peripheral fatty acids to the development of hepatic steatosis in NAFLD.