Elizabeth J Parks

University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Publications (47)331.2 Total impact

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    ABSTRACT: There have been few studies on the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between individuals with NAFLD and those without, matched for metabolic factors (controls). We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n=13) or low levels of intrahepatic triacylglycerol (LowLF, n=11). Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (non-esterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis. Individuals with HighLF (18.4%±3.6%) had higher plasma levels of FFA during the nighttime and concentrations of insulin than subjects with LowLF (3.1%±2.7%; P=.04 and P<.001, respectively). No differences were observed between groups in adipose flux of FFA (414±195 μmol/min for HighLF vs 358±105 μmol/min for LowLF; P=.41) or production of very low-density lipoprotein triacylglycerols from FFA (4.06±2.57 μmol/min vs 4.34±1.82 μmol/min; P=.77). By contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57±1.53 μmol/min vs 0.78±0.42 μmol/min; P=.001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2%±7.9% vs 10.1%±6.7%; P<.001); this level was independently associated with the level of intrahepatic triacylglycerol (r=0.53; P=.007). By administering isotopes to individuals with NAFLD and control subjects, we confirmed that those with NAFLD increase synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFA and did not suppress the contribution from de novo lipogenesis upon fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.
    Gastroenterology 12/2013; · 12.82 Impact Factor
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    ABSTRACT: The goal of this study was to determine whether administration of the CB(1) cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons (Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d(31)-tripalmitin) and intravenously ((13)C(4)-palmitate, (13)C(1)-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals (P < 0.04), glucose disposal increased 30% (P = 0.03), and FFA turnover increased 37% (P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg(-1)·h(-1), P = 0.03). These data support the potential for a strong effect of CB(1) receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis.
    AJP Endocrinology and Metabolism 07/2012; 303(5):E624-34. · 4.51 Impact Factor
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    ABSTRACT: Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. The goal of the present study was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics. Fatty acid kinetics were measured during a meal tolerance test and insulin sensitivity assessed by intravenous glucose tolerance test in overweight human subjects (n=15; body mass index, 35.8 ± 7.1 kg/m(2)). Non-steady state tracer kinetic models were formulated and tested using ProcessDB software. Suppression of adipose fatty acid release, by itself, could not account for postprandial nonesterified fatty acid concentration changes, but adipose suppression combined with insulin activation of fatty acid uptake was consistent with the measured data. The observed insulin K(m) for nonesterified fatty acid uptake was inversely correlated with both insulin sensitivity of glucose uptake (intravenous glucose tolerance test insulin sensitivity; r=-0.626; P=0.01) and whole body fat oxidation after the meal (r=-0.538; P=0.05). These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2012; 32(8):1799-808. · 6.34 Impact Factor
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    Jennifer E Lambert, Elizabeth J Parks
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    ABSTRACT: The intake of dietary fat above energy needs has contributed to the growing rates of obesity worldwide. The concept of disease development occurring in the fed state now has much support and dysregulation of substrate flux may occur due to poor handling of dietary fat in the immediate postprandial period. The present paper will review recent observations implicating cephalic phase events in the control of enterocyte lipid transport, the impact of varying the composition of meals on subsequent fat metabolism, and the means by which dietary lipid carried in chylomicrons can lead to elevated postprandial non-esterified fatty acid concentrations. This discussion is followed by an evaluation of the data on quantitative meal fat oxidation at the whole body level and an examination of dietary fat clearance to peripheral tissues - with particular attention paid to skeletal muscle and liver given the role of ectopic lipid deposition in insulin resistance. Estimates derived from data of dietary-TG clearance show good agreement with clearance to the liver equaling 8-12% of meal fat in lean subjects and this number appears higher (10-16%) in subjects with diabetes and fatty liver disease. Finally, we discuss new methods with which to study dietary fatty acid partitioning in vivo. Future research is needed to include a more comprehensive understanding of 1) the potential for differential oxidation of saturated versus unsaturated fatty acids which might lead to meaningful energy deficit and whether this parameter varies based on insulin sensitivity, 2) whether compartmentalization exists for diet-derived fatty acids within tissues vs. intracellular pools, and 3) the role of reduced peripheral fatty acid clearance in the development of fatty liver disease. Further advancements in the quantitation of dietary fat absorption and disposal will be central to the development of therapies designed to treat diet-induced obesity. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
    Biochimica et Biophysica Acta 05/2012; 1821(5):721-6. · 4.66 Impact Factor
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    ABSTRACT: Approximately one-third of the U.S. population has nonalcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance and increased risk of liver injury. Dysregulated mitochondrial metabolism is central in these disorders, but the manner and degree of dysregulation are disputed. This study tested whether humans with NAFLD have abnormal in vivo hepatic mitochondrial metabolism. Subjects with low (3.0%) and high (17%) intrahepatic triglyceride (IHTG) were studied using (2)H and (13)C tracers to evaluate systemic lipolysis, hepatic glucose production, and mitochondrial pathways (TCA cycle, anaplerosis, and ketogenesis). Individuals with NAFLD had 50% higher rates of lipolysis and 30% higher rates of gluconeogenesis. There was a positive correlation between IHTG content and both mitochondrial oxidative and anaplerotic fluxes. These data indicate that mitochondrial oxidative metabolism is ~2-fold greater in those with NAFLD, providing a potential link between IHTG content, oxidative stress, and liver damage.
    Cell metabolism 12/2011; 14(6):804-10. · 17.35 Impact Factor
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    ABSTRACT: Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.
    Endocrinology 11/2011; 153(1):113-22. · 4.72 Impact Factor
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    ABSTRACT: This study determined whether reductions in postprandial plasma nonesterified fatty acid (FFA) flux would lead to reductions in plasma acylcarnitine (AC) concentrations. Plasma AC was measured by liquid chromatography with tandem mass spectrometry in the fasting state and over 6 hours after a high-fat (50% energy) meal was fed to 16 overweight and obese subjects with a wide range of insulin sensitivities. Body composition was measured by dual-energy x-ray absorptiometry; insulin sensitivity by insulin-modified, frequently sampled intravenous glucose tolerance test; substrate oxidation by indirect calorimetry; blood metabolite and hormone concentrations biochemically; and fatty acid flux by using stable isotope tracers. Lean body mass and fasting fat oxidation correlated positively (r > 0.522, P < .05), whereas glucose oxidation correlated negatively (r < -0.551, P < .04), with fasting AC. Postprandially, plasma glucose, insulin, and triglyceride concentrations increased; and FFA concentrations decreased significantly. The responses of plasma AC species depended on chain length and saturation, with C14:0, C16:0, and C18:0 remaining unchanged, and unsaturated species (eg, C14:1, C14:2) falling significantly (21%-46%, P < .03). Postmeal nadir AC concentrations were positively associated with lean body mass, postprandial fatty acid flux, and FFA concentrations (r > 0.515, P < .05). By contrast, nadir AC correlated negatively with insulin sensitivity and spillover of meal-derived fatty acids (r < -0.528, P < .04). Conditions that impact fatty acid flux contribute to the control of postprandial plasma AC concentrations. These data underscore the need for a better understanding of postprandial fatty acid oxidation and dietary fat delivery in the setting of adipose insulin resistance to determine how postprandial lipemia contributes to chronic disease risk.
    Metabolism: clinical and experimental 08/2011; 61(2):202-12. · 3.10 Impact Factor
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    ABSTRACT: Recognition of the strength of nonhuman primate models in investigating metabolic disorders has resulted in an expanded need for in vivo research techniques. We studied adipose metabolism in 10 baboons (13.0 ± 4.2 years old, 29.5 ± 5.5 kg). Part 1 evaluated the effect of different sedatives on the rate of appearance of plasma free fatty acids (RaFFA), assessed using ¹³C₄-labeled palmitate infusion (7 µmol/kg/min). Animals, were studied with no sedation, with complete isoflurane sedation, and with minimal midazolam infusion (0.04 mg/kg/h), with the last scheme allowing for the most consistent values and animals that were visually more calm. In Part 2, RaFFA and RaGlycerol (D₅-glycerol, 5 mg/kg lean body mass/h) were measured. From midnight to 0300, flux fell and came to a steady state between 0500 and 0700 h (RaFFA, 39.4 ± 29.8 μmol/kg fat mass/min; and RaGlycerol, 26.9 ± 7.3 μmol/kg/min). The RaFFA-to-RaGlycerol ratio was 1.5 ± 0.8 (49% reesterification). The decline in turnover throughout the night reflects natural circadian processes and was mirrored by reductions in FFA and glycerol to 0.62 and ± 0.14 and 0.16 and ± 0.03 mmol/l, respectively. The concurrent changes in both FFA and glycerol kinetics indicate physiologic validity of the method. These techniques will support needed research to determine mechanisms by which treatments act upon the adipocyte in vivo.
    The Journal of Lipid Research 03/2011; 52(6):1272-80. · 4.39 Impact Factor
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    ABSTRACT: Given the importance of postprandial hyperlipidemia to increase risk for atherosclerosis, in the present study, stable isotope-labeled meals were fed to healthy subjects (7 males and 3 females) to investigate the kinetics chylomicron synthesis and the effect of sensory exposure to lipid on metabolism. Subjects performed two, 24-hour inpatient studies that entailed consumption of a liquid formula evening meal containing 30 g of oil (+ (13)C(2) triolein) on day 1. Breakfast (day 2) consisted of triacylglycerols (TAGs) fed as capsules (30 g oil + (13)C(7) triolein) to avoid activation of mouth taste receptors. Next, modified sham feeding of cream cheese occurred over 2 hours. In the 2 trials, the stimulus was either higher fat (HF) or lower fat (LF) cream cheese. A liquid meal was consumed at lunch. Blood sampling occurred intermittently, and chylomicron particles S(f) >400 TAGs were analyzed by gas chromatography-mass spectrometry. (13)C(2)-Label was found in fasting-state lipoproteins, and persons with higher body fat percentages showed greater dilution of meal TAGs from endogenous sources. For both trials, 13% ± 4% of lipoprotein TAGs oleic acid was derived from the previous evening meal. Incremental area under the curve for TAGs during HF was ∼2.5 times higher than after LF exposure (46 ± 15 vs 17 ± 5 μmol/L/h; P = .04). The greater HF morning lipemia occurred with elevated glucose, insulin, and nonesterified fatty acids peak after lunch. These data support a connection between enteral lipid metabolism and oral fat exposure, resulting in elevated postprandial lipemia. The results suggest that the intestine may participate in a mechanism coordinating oral fat signaling with control of subsequent macronutrient disposal in the body.
    Gastroenterology 11/2010; 139(5):1538-48. · 12.82 Impact Factor
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    ABSTRACT: We evaluate a potential role of activating transcription factor 4 (Atf4) in invertebrate and mammalian metabolism. With two parallel approaches-a fat body-specific green fluorescent protein enhancer trap screen in D. melanogaster and expression profiling of developing murine fat tissues-we identified Atf4 as expressed in invertebrate and vertebrate metabolic tissues. We assessed the functional relevance of the evolutionarily conserved expression by analyzing Atf4 mutant flies and Atf4 mutant mice for possible metabolic phenotypes. Flies with insertions at the Atf4 locus have reduced fat content, increased starvation sensitivity, and lower levels of circulating carbohydrate. Atf4 null mice are also lean, and they resist age-related and diet-induced obesity. Atf4 null mice have increased energy expenditure potentially accounting for the lean phenotype. Atf4 null mice are hypoglycemic, even before substantial changes in fat content, indicating that Atf4 regulates mammalian carbohydrate metabolism. In addition, the Atf4 mutation blunts diet-induced diabetes as well as hyperlipidemia and hepatosteatosis. Several aspects of the Atf4 mutant phenotype resemble mice with mutations in components of the target of rapamycin (TOR) pathway. Consistent with the phenotypic similarities, Atf4 null mice have reduced expression of genes that regulate intracellular amino acid concentrations and lower intracellular concentration of amino acids, a key TOR input. Further, Atf4 mutants have reduced S6K activity in liver and adipose tissues. Atf4 regulates age-related and diet-induced obesity as well as glucose homeostasis in mammals and has conserved metabolic functions in flies.
    Diabetes 09/2009; 58(11):2565-73. · 7.90 Impact Factor
  • Aldo Grefhorst, Elizabeth J Parks
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    ABSTRACT: The nuclear liver X receptor (LXR) regulates multiple aspects of cholesterol, triacylglycerol (TG), and carbohydrate metabolism. Activation of LXR induces the expression of genes encoding enzymes involved in de novo lipogenesis (DNL) resulting in hepatic steatosis in mice. Pharmacological LXR activation has also been reported to improve insulin sensitivity and glucose homeostasis in diabetic rodents. The effects of pharmacological LXR ligands on insulin's action on hepatic lipid metabolism are not known. We evaluated secretion of VLDL during a hyperinsulinemic euglycemic clamp in mice treated with the LXR-ligand T0901317. In untreated mice, hyperinsulinemia reduced the availability of plasma NEFA for VLDL-TG synthesis, increased the contribution of DNL to VLDL-TG, reduced VLDL particle size, and suppressed overall VLDL-TG production rate by approximately 50%. Upon T0901317 treatment, hyperinsulinemia failed to reduce VLDL particle size or suppress VLDL-TG production rate, but the contribution of DNL to VLDL-TG was increased. In conclusion, the effects of LXR activation by T0901317 on lipid metabolism can override the normal control of insulin to suppress VLDL particle secretion.
    The Journal of Lipid Research 04/2009; 50(7):1374-83. · 4.39 Impact Factor
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    ABSTRACT: The goal of this study was to determine the magnitude by which acute consumption of fructose in a morning bolus would stimulate lipogenesis (measured by infusion of 13C1-acetate and analysis by GC-MS) immediately and after a subsequent meal. Six healthy subjects [4 men and 2 women; aged (mean +/- SD) 28 +/- 8 y; BMI, 24.3 +/- 2.8 kg/m(2); and serum triacylglycerols (TG), 1.03 +/- 0.32 mmol/L] consumed carbohydrate boluses of sugars (85 g each) in a random and blinded order, followed by a standardized lunch 4 h later. Subjects completed a control test of glucose (100:0) and a mixture of 50:50 glucose:fructose and one of 25:75 (wt:wt). Following the morning boluses, serum glucose and insulin after 100:0 were greater than both other treatments (P < 0.05) and this pattern occurred again after lunch. In the morning, fractional lipogenesis was stimulated when subjects ingested fructose and peaked at 15.9 +/- 5.4% after the 50:50 treatment and at 16.9 +/- 5.2% after the 25:75 treatment, values that were greater than after the 100:0 treatment (7.8 +/- 5.7%; P < 0.02). When fructose was consumed, absolute lipogenesis was 2-fold greater than when it was absent (100:0). Postlunch, serum TG were 11-29% greater than 100:0 and TG-rich lipoprotein-TG concentrations were 76-200% greater after 50:50 and 25:75 were consumed (P < 0.05). The data demonstrate that an early stimulation of lipogenesis after fructose, consumed in a mixture of sugars, augments subsequent postprandial lipemia. The postlunch blood TG elevation was only partially due to carry-over from the morning. Acute intake of fructose stimulates lipogenesis and may create a metabolic milieu that enhances subsequent esterification of fatty acids flowing to the liver to elevate TG synthesis postprandially.
    Journal of Nutrition 06/2008; 138(6):1039-46. · 4.20 Impact Factor
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    Elizabeth J Parks, Marc K Hellerstein
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    ABSTRACT: Isotopic measurement of biosynthetic rates of lipids in VLDL particles has long posed difficult technical problems. In this review, key methodologic issues and recent technical advances are discussed. A common problem for all biosynthetic measurements is the requirement to measure isotopic labeling of the true intracellular biosynthetic precursor pool. Two techniques that address this problem for lipid biosynthesis, and that are applicable to humans, have been developed-the combinatorial probability method (or mass isotopomer distribution analysis) and (2)H(2)O incorporation. The theoretical basis and practical application of these methods, both of which involve mass spectrometry, are described. Issues relevant to specific lipid components of VLDL, such as differences in the labeling of the various particle lipids (phospholipid, cholesterol, etc.), and the contribution of an intrahepatic cytosolic triacylglycerol (TG) storage pool to VLDL-TG are discussed. In summary, advances in stable isotope-mass spectrometric techniques now permit accurate measurement of liver-TG synthesis and flux. In vivo regulation of the synthesis, assembly, and secretion of VLDL-TG in humans is thereby accessible to direct investigation. Patient-oriented research in conditions such as dyslipidemia and hepatic steatosis is made feasible by these scientific advances.
    The Journal of Lipid Research 09/2006; 47(8):1651-60. · 4.39 Impact Factor
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    Brian R Barrows, Elizabeth J Parks
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    ABSTRACT: The liver's regulation of fatty acids (FAs) postprandially may contribute to risk of metabolic diseases. Measurements of steady-state metabolism were used to investigate sources of FAs used for very low-density lipoprotein (VLDL)-triacylglycerol (TG) synthesis during fasting and feeding in vivo. Subjects were duodenally fed a formula labeled with the stable isotope glyceryl tri-palmitate-d(31) and iv infused with [1,2,3,4-(13)C(4)]-palmitatic acid and [1-(13)C(1)]-acetate to quantitate the liver's use of FAs originating from adipose tissue and de novo lipogenesis. This study of healthy men (n = 12; body mass index, 24.4 +/- 2.7 kg/m(2)) was conducted at a General Clinical Research Center. Concentrations of metabolites during fasting and feeding, sources of FAs used for lipoprotein synthesis, rate of appearance of serum nonesterified FA (NEFA), and VLDL-TG were measured. During fasting, 77.2 +/- 14.0% of VLDL-TG was derived from adipose FA recycling and 4.0 +/- 3.6% from lipogenesis; with feeding, 43.6 +/- 18.6% came from adipose FAs (P < 0.001), 8.2 +/- 5.1% from lipogenesis (P < 0.001), 15.2 +/- 13.7% from uptake of chylomicron-remnant TG, and 10.3 +/- 6.9% from dietary FA spillover into the serum NEFA pool. Fed-state VLDL-TG from NEFA reesterification decreased in proportion to the reduction in adipose NEFA appearance. These data: 1) quantify the extent to which the healthy liver manages its use of different sources of FAs that flow to it, 2) demonstrate how the postprandial reduction in adipose-NEFA flux may be partially replaced by other sources, and 3) highlight the potential for dietary FA spillover to support the continued dominance of NEFA as a substrate for VLDL-TG synthesis.
    Journal of Clinical Endocrinology &amp Metabolism 04/2006; 91(4):1446-52. · 6.43 Impact Factor
  • Brian R Barrows, Maureen T Timlin, Elizabeth J Parks
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    ABSTRACT: The present study quantified dietary fatty acid flux in healthy men (n = 6) who were fed a liquid formula through a duodenal feeding tube (continuous feeding group) or who consumed the same formula in meals (meal feeding group). A triacylglycerol (TAG) stable isotope was added to the formula to determine the entry of dietary fatty acids into the serum and its clearance to the liver and resecretion into serum via VLDL. The contribution of dietary fatty acids to serum nonesterified fatty acids (NEFAs) was higher with meal feeding (24.4 +/- 2.6%) compared with continuous feeding (10.8 +/- 2.9%, P < 0.01) and, when multiplied by the NEFA concentration, resulted in similar absolute fatty acid spillover. Diet-derived NEFAs subsequently represented 10.6 +/- 1.2% and 4.7 +/- 1.3% of hepatic VLDL-TAG (meal feeding vs. continuous feeding, respectively, P = 0.004). Chylomicron remnant uptake by the liver contributed 9.3 +/- 1.9% of fatty acids to hepatic VLDL-TAG synthesis with meal feeding compared with continuous feeding (4.4 +/- 0.8%, P < 0.03). These data suggest that the extent of dietary fatty acid recycling via serum NEFAs and VLDL-TAG is determined by the rate of delivery of dietary fat to the intestine. The inefficient removal of dietary fat from the circulation may maintain VLDL-TAG production but may also result in prolonged postprandial lipemia.
    Diabetes 10/2005; 54(9):2668-73. · 7.90 Impact Factor
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    Maureen T Timlin, Brian R Barrows, Elizabeth J Parks
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    ABSTRACT: Sources of fatty acids flowing to the liver may be used for triacylglycerol (TAG) synthesis. Our objective was to quantify contributions of nonesterified fatty acids (NEFAs), de novo lipogenesis, and dietary fatty acids to VLDL-TAG in the fed state after meal feeding in healthy subjects (n = 6). The effect of substrate delivery rate was also determined by comparison with data obtained under a continuous-feeding regimen. A liquid diet was administered by mouth or via feeding tube. Contributions of NEFAs, de novo lipogenesis, and dietary fatty acids to VLDL-TAG were quantified using stable isotopes and gas chromatography-mass spectrometry. Contribution of NEFAs to VLDL-TAG was similar under meal feeding and continuous feeding, although insulin area under the curve (AUC) was greater under meal feeding (1,597 +/- 455 vs. 471 +/- 484 pmol . h . l(-1), P < 0.004). Lipogenesis achieved a higher AUC with meal feeding versus continuous feeding (88.7 +/- 84.4 vs. 1.9 +/- 19.3 mumol . h . l(-1), P = 0.03) supporting greater stimulation of de novo lipogenesis from increased glucose delivery rate. The contribution of dietary fatty acids to VLDL-TAG was also greater with meal feeding. These data demonstrate for the first time in humans the well-coordinated use of fatty acids by the liver during the transition from fasted to fed states and highlight the dominant role of NEFAs for VLDL-TAG synthesis in both states.
    Diabetes 10/2005; 54(9):2694-701. · 7.90 Impact Factor
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    ABSTRACT: We generated a Spot 14 null mouse to assess the role of Spot 14 in de novo lipid synthesis and report the Spot 14 null mouse exhibits a phenotype in the lactating mammary gland. Spot 14 null pups nursed by Spot 14 null dams gain significantly less weight than wild-type pups nursed by wild-type dams. In contrast, Spot 14 null pups nursed by heterozygous dams show similar weight gain to wild-type littermates. We found the triglyceride content in Spot 14 null milk is significantly reduced. We demonstrate this reduction is the direct result of decreased de novo lipid synthesis in lactating mammary glands, corroborated by a marked reduction of medium-chain fatty acids in the triglyceride pool. Importantly, the reduced lipogenic rate is not associated with significant changes in the activities or mRNA of key lipogenic enzymes. Finally, we report the expression of a Spot 14-related gene in liver and adipose tissue, which is absent in the lactating mammary gland. We suggest that expression of both the Spot 14 and Spot 14-related proteins is required for maximum efficiency of de novo lipid synthesis in vivo and that these proteins impart a novel mechanism regulating de novo lipogenesis.
    Endocrinology 09/2005; 146(8):3343-50. · 4.72 Impact Factor
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    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.
    Journal of Clinical Investigation 06/2005; 115(5):1343-51. · 12.81 Impact Factor
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    Gary E Truett, Elizabeth J Parks
    Journal of Nutrition 06/2005; 135(5):1313. · 4.20 Impact Factor
  • Elizabeth Jane Parks, Tara Lynn Schneider, Rachel Ann Baar
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    ABSTRACT: To identify optimal study-design conditions to investigate lipid metabolism, male, C57BL/6J mice (age, 59 +/- 3 days) were allotted to eight groups, with six animals per group that were stratified by three factors: diet type (high fat [HF]: 60% of energy from fat versus that of a standard rodent diet, 14% fat, fed for 7 weeks), feeding regimen (ad libitum [ad lib] versus meal fed), and metabolic state (data collected in fasted or fed states). Serum free fatty acids (FFA) and triacylglycerols (TAG) concentrations, and energy expenditure (EE) were assessed. Mice gained 0.30 +/- 0.11 g of body weight/day when allowed ad lib access to HF diet, similar weight when meal-fed the HF or ad lib-fed the standard diet (0.10 +/- 0.03 g/day), and no weight when meal-fed the standard diet (0.01 +/- 0.02 g/day). Fed-state TAG concentration was 88 to 100% higher (P < 0.02) than that of the fasted state, except when animals were ad lib-fed the HF diet. When the standard diet was meal fed, FFA concentration was 30% higher in the fasted compared with the fed state (P = 0.003). Mice had 33% higher postprandial EE when either diet was meal fed (P = 0.01). Mice adapted to meal feeding developed transitions in metabolism consistent with known physiologic changes that occur from fasting to feeding. When fed the standard diet, a 6-h per day meal-feeding regimen was restrictive for normal growth. These data support use of a meal-feeding regimen when HF diets are used and research is focused on metabolic differences between fasted and fed states. This protocol allows study of the metabolic effects of an HF diet without the confounding effects of over-consumption of food and excess body weight gain.
    Comparative medicine 02/2005; 55(1):24-9. · 1.12 Impact Factor

Publication Stats

2k Citations
331.20 Total Impact Points


  • 2006–2013
    • University of Texas Southwestern Medical Center
      • • Department of Internal Medicine
      • • Center for Human Nutrition
      Dallas, Texas, United States
  • 2011
    • Texas Biomedical Research Institute
      • Department of Genetics
      San Antonio, TX, United States
  • 2010
    • Children's Medical Center Dallas
      Dallas, Texas, United States
  • 2009
    • University of Groningen
      • Department of Pediatrics
      Groningen, Province of Groningen, Netherlands
  • 2000–2006
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2005
    • University of Tennessee
      • Department of Nutrition
      Knoxville, TN, United States
  • 1999–2004
    • University of Minnesota Twin Cities
      • Department of Food Science and Nutrition
      Minneapolis, MN, United States
    • University of California, Berkeley
      • Department of Nutritional Science and Toxicology
      Berkeley, MO, United States
  • 1998–2001
    • University of California, Davis
      • Department of Nutrition
      Davis, CA, United States