scholarly journals Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene

2015 ◽  
Vol 100 (8) ◽  
pp. E1125-E1132 ◽  
Author(s):  
Nicola Santoro ◽  
Sonia Caprio ◽  
Bridget Pierpont ◽  
Michelle Van Name ◽  
Mary Savoye ◽  
...  
Keyword(s):  
Glucose Oxidation ◽  
De Novo ◽  
Liver Lipid ◽  
Low Density Lipoprotein ◽  
Lipid Synthesis ◽  
Area Under The Curve ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Obese Youth ◽  
Lower Ability

Objective: This study's aim was to evaluate whether the GCKR rs1260326 variant increases hepatic de novo lipogenesis (DNL). Setting and Design: To test this hypothesis, 14 adolescents, seven homozygous for the common allele (CC) and seven homozygous for the risk allele (TT), underwent measurement of hepatic DNL during the fasting state and after consumption of a carbohydrate (CHO) drink (75 g glucose and 25 g fructose). DNL was assessed through incorporation of deuterium in the palmitate contained in the very low-density lipoprotein. Results: Subjects with TT demonstrated higher fasting fractional DNL (P = .036) and a lower increase in fractional DNL after the CHO challenge (P = .016). With regard to absolute lipogenesis, TT subjects had both higher fasting rates (P = .015) and 44% greater area under the curve of absolute lipogenesis during the study (P = .016), compared to CC subjects. Furthermore, subjects carrying the TT genotype showed higher basal rates of glucose oxidation (P = .0028) and a lower ability than CC subjects to increase the rates of glucose oxidation after the CHO load (P = .054). Conclusions: This study reports for the first time rates of DNL in obese adolescents and suggests that the GCKR rs1260326 gene variant, which is associated with greater glycolysis, increases hepatic DNL. These data highlight the role of glycolytic carbon flux in liver lipid synthesis and hypertriglyceridemia in these youngsters.

scholarly journals Fasting hepatic de novo lipogenesis is not reliably assessed using circulating fatty acid markers

2019 ◽  
Vol 109 (2) ◽  
pp. 260-268 ◽  
Author(s):  
Fredrik Rosqvist ◽  
Catriona A McNeil ◽  
Camilla Pramfalk ◽  
Sion A Parry ◽  
Wee Suan Low ◽  
...  
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
De Novo Lipogenesis ◽  
Deuterated Water ◽  
Lipid Fractions ◽  
Habitual Diet ◽  
Fa Markers

ABSTRACT Background Observational studies often infer hepatic de novo lipogenesis (DNL) by measuring circulating fatty acid (FA) markers; however, it remains to be elucidated whether these markers accurately reflect hepatic DNL. Objectives We investigated associations between fasting hepatic DNL and proposed FA markers of DNL in subjects consuming their habitual diet. Methods Fasting hepatic DNL was assessed using 2H2O (deuterated water) in 149 nondiabetic men and women and measuring the synthesis of very low-density lipoprotein triglyceride (VLDL-TG) palmitate. FA markers of blood lipid fractions were determined by gas chromatography. Results Neither the lipogenic index (16:0/18:2n–6) nor the SCD index (16:1n–7/16:0) in VLDL-TG was associated with isotopically assessed DNL (r = 0.13, P = 0.1 and r = −0.08, P = 0.35, respectively). The relative abundances (mol%) of 14:0, 16:0, and 18:0 in VLDL-TG were weakly (r ≤ 0.35) associated with DNL, whereas the abundances of 16:1n–7, 18:1n–7, and 18:1n–9 were not associated. When the cohort was split by median DNL, only the abundances of 14:0 and 18:0 in VLDL-TG could discriminate between subjects having high (11.5%) and low (3.8%) fasting hepatic DNL. Based on a subgroup, FA markers in total plasma TG, plasma cholesteryl esters, plasma phospholipids, and red blood cell phospholipids were generally not associated with DNL. Conclusions The usefulness of circulating FAs as markers of hepatic DNL in healthy individuals consuming their habitual diet is limited due to their inability to discriminate clearly between individuals with low and high fasting hepatic DNL.

scholarly journals The Effect of Fructose Feeding on Intestinal Triacylglycerol Production and De Novo Fatty Acid Synthesis in Humans

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1781
Author(s):  
Simon Steenson ◽  
Fariba Shojaee-Moradie ◽  
Martin B. Whyte ◽  
Kim G. Jackson ◽  
Julie A. Lovegrove ◽  
...  
Keyword(s):  
De Novo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Acute Effect ◽  
De Novo Lipogenesis ◽  
Fructose Intake ◽  
High Fructose ◽  
Catabolic Rate

A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 h. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (p < 0.005) and VLDL-TAG (p = 0.003) were greater, and CM-TAG production rate (PR, p = 0.046) and CM-TAG fractional catabolic rate (FCR, p = 0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (p = 0.005) and apoB48 (p = 0.039), apoB100 (p = 0.013) and non-esterified fatty acids (NEFA) (p = 0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (p = 0.043) and low-fructose (p = 0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase.

scholarly journals Hepatic ANGPTL3 regulates adipose tissue energy homeostasis

2015 ◽  
Vol 112 (37) ◽  
pp. 11630-11635 ◽  
Author(s):  
Yan Wang ◽  
Markey C. McNutt ◽  
Serena Banfi ◽  
Michael G. Levin ◽  
William L. Holland ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
De Novo ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Fed State ◽  
Beneficial Effects ◽  
Brown Adipose

Angiopoietin-like protein 3 (ANGPTL3) is a circulating inhibitor of lipoprotein and endothelial lipase whose physiological function has remained obscure. Here we show that ANGPTL3 plays a major role in promoting uptake of circulating very low density lipoprotein-triglycerides (VLDL-TGs) into white adipose tissue (WAT) rather than oxidative tissues (skeletal muscle, heart brown adipose tissue) in the fed state. This conclusion emerged from studies of Angptl3−/− mice. Whereas feeding increased VLDL-TG uptake into WAT eightfold in wild-type mice, no increase occurred in fed Angptl3−/− animals. Despite the reduction in delivery to and retention of TG in WAT, fat mass was largely preserved by a compensatory increase in de novo lipogenesis in Angptl3−/− mice. Glucose uptake into WAT was increased 10-fold in KO mice, and tracer studies revealed increased conversion of glucose to fatty acids in WAT but not liver. It is likely that the increased uptake of glucose into WAT explains the increased insulin sensitivity associated with inactivation of ANGPTL3. The beneficial effects of ANGPTL3 deficiency on both glucose and lipoprotein metabolism make it an attractive therapeutic target.

Lipid processing and lipoprotein synthesis by the developing human fetal colon

1996 ◽  
Vol 270 (5) ◽  
pp. G813-G820 ◽  
Author(s):  
E. Levy ◽  
N. Loirdighi ◽  
L. Thibault ◽  
T. D. Nguyen ◽  
D. Labuda ◽  
...  
Keyword(s):  
Oleic Acid ◽  
De Novo ◽  
Low Density Lipoprotein ◽  
Lipid Synthesis ◽  
Density Lipoprotein ◽  
Secretory Process ◽  
Mrna Editing ◽  
Major Purpose ◽  
Apo B ◽  
First Time

Despite significant progress in the elucidation of the ontogeny of gastrointestinal function, little attention has been given to colonic lipid processing during development. The major purpose of this study was to explore the intracellular phase of fat absorption, lipid synthesis, and secretion in the human fetal colon compared with the jejunum originating from the same fetuses. The synthesis of lipids and major apolipoproteins was examined using cultured fetal colonic explants incubated with [14C]oleic acid and [36S]methionine, respectively. Fetal colonic explants demonstrated substantial ability to incorporate [14C]oleic acid (dpm/mg protein) into phospholipids (48,743 +/- 4,783), triglycerides (25,687 +/- 2,469), and cholesteryl esters (6,751 +/- 1,227). The total amount of radiolabeled lipids was much higher within the tissue (87,472 +/- 9,142) than in the medium (51,916 +/- 4,970), indicating a limited capacity of the fetal colon to export newly synthesized lipids. The limited colonic lipid secretory process was even more evident when compared with homologous fetal jejunal de novo synthesized lipids in tissue (133,975 +/- 13,836) and medium (279,858 +/- 1,610), respectively. Similar to the jejunum, the colon was able to elaborate all the phospholipid classes, with phosphatidylcholine accounting for > 70% of tissue phospholipids. However, their individual levels were present in lesser amounts in the colon (P > 0.001). Colonic explants elaborated most of the major lipoprotein classes but were less efficient than jejunal explants in exporting chylomicrons (33-fold), very low density lipoprotein (1.5-fold), and high-density lipoprotein (9-fold) into the medium. Apolipoprotein (apo) B synthesis and apo B mRNA editing were comparable in colonic and jejunal explants; thus they are not responsible for the defective lipoprotein secretion in the fetal large bowel. These results establish for the first time te capability of the human fetal colon to form, but not to efficiently transport, lipids, lipoproteins, and apoproteins.

scholarly journals A Dual Sugar Challenge Test for Lipogenic Sensitivity to Dietary Fructose

2011 ◽  
Vol 96 (3) ◽  
pp. 861-868 ◽  
Author(s):  
Lisa C. Hudgins ◽  
Thomas S. Parker ◽  
Daniel M. Levine ◽  
Marc K. Hellerstein
Keyword(s):  
De Novo ◽  
Low Density Lipoprotein ◽  
Challenge Test ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Dose Effect ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Repeated Doses ◽  
Dietary Sugar

Context: Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in dyslipidemia, fatty liver, and insulin resistance. Objective: The aim of the study was to develop a simple outpatient tolerance test for lipogenic sensitivity to dietary sugar. Design and Setting: In inpatients given repeated doses of fructose, protocol 1 compared the acute increase in DNL determined from the percentage of palmitate (“new palmitate”) and the percentage of isotopically labeled palmitate (“%DNL”) in very low-density lipoprotein triglyceride (TG). Protocol 2 compared the increase in new palmitate in outpatients given three different sugar beverages in a randomized crossover design. Participants: There were 15 lean and overweight volunteers in protocol 1 and 15 overweight volunteers in protocol 2. Interventions: In protocol 1, subjects received 1.4 g/kg fructose in divided oral doses over 6 h; in protocol 2, subjects received 0.5 g/kg fructose, 0.5 g/kg fructose plus 0.5g/kg glucose, or 1 g/kg fructose plus 1g/kg glucose each as a single oral bolus. Main Outcome Measures: We measured the increase in DNL by two methods. Results: After repeated doses of fructose, new palmitate was significantly correlated with the increase in %DNL (Δ, r = 0.814; P &lt; 0.001) and with fasting insulin levels (area under the curve, r = 0.754; P = 0.001). After a single sugar dose, new palmitate showed a dose effect and was greater after fructose plus glucose. Very low-density lipoprotein TG and total TG significantly increased in both protocols. Conclusions: A single oral bolus of fructose and glucose rapidly increases serum TG and TG palmitate in overweight subjects. A dual sugar challenge test could prove useful to identify individuals at risk for carbohydrate-induced dyslipidemia and other adverse effects of increased DNL.

scholarly journals The role of ATP citrate-lyase in the metabolic regulation of plasma lipids

1998 ◽  
Vol 334 (1) ◽  
pp. 113-119 ◽  
Author(s):  
Nigel J. PEARCE ◽  
John W. YATES ◽  
Theo A. BERKHOUT ◽  
Brian JACKSON ◽  
David TEW ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Lipid Synthesis ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Atp Citrate Lyase ◽  
Cholesterol Levels ◽  
Citrate Lyase

ATP citrate (pro-S)-lyase (EC 4.1.3.8), a cytosolic enzyme that generates acetyl-CoA for cholesterol and fatty acid synthesis de novo, is a potential target for hypolipidaemic intervention. Here we describe the biological effects of the inhibition of ATP citrate-lyase on lipid metabolism in Hep G2 cells, and plasma lipids in rats and dogs, by using SB-204990, the cell-penetrant γ-lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076 (Ki = 1 µM). Consistent with an important role of ATP citrate-lyase in the supply of acetyl-CoA units for lipid synthesis de novo, SB-204990 inhibited cholesterol synthesis and fatty acid synthesis in Hep G2 cells (dose-related inhibition of up to 91% and 82% respectively) and rats (76% and 39% respectively). SB-204990, when administered orally to rats, was absorbed into the systemic circulation; pharmacologically relevant concentrations of SB-201076 were recovered in the liver. When administered in the diet (0.05–0.25%, w/w) for 1 week, SB-204990 caused a dose-related decrease in plasma cholesterol (by up to 46%) and triglyceride levels (by up to 80%) in rats. This hypolipidaemic effect could be explained, at least in part, by a decrease (up to 48%) in hepatic very-low-density lipoprotein (VLDL) production as measured by the accumulation of VLDL in plasma after injection of Triton WR-1339. SB-204990 (25 mg/kg per day) also decreased plasma cholesterol levels (by up to 23%) and triglyceride levels (by up to 38%) in the dog, preferentially decreasing low-density lipoprotein compared with high-density lipoprotein cholesterol levels. Overall these results are consistent with the concept that ATP citrate-lyase is an important enzyme in controlling substrate supply for lipid synthesis de novo and a potential enzyme target for hypolipidaemic intervention.

scholarly journals Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1181
Author(s):  
Raffaella Soleti ◽  
Marine Coué ◽  
Charlotte Trenteseaux ◽  
Gregory Hilairet ◽  
Lionel Fizanne ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Aortic Root ◽  
De Novo ◽  
Body Weight Gain ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Hemodynamic Parameters ◽  
Cellular Models ◽  
Genetic Mouse Model

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

scholarly journals Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009891
Author(s):  
Baocai Xie ◽  
Xiaochen Shi ◽  
Yan Li ◽  
Bo Xia ◽  
Jia Zhou ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherogenic Diet ◽  
Standard Diet ◽  
Low Levels ◽  
Reduced Risk

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.

scholarly journals Regular exercise potentiates energetically expensive hepatic de novo lipogenesis during early weight regain

2019 ◽  
Vol 317 (5) ◽  
pp. R684-R695
Author(s):  
David M. Presby ◽  
L. Allyson Checkley ◽  
Matthew R. Jackman ◽  
Janine A. Higgins ◽  
Kenneth L. Jones ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
De Novo ◽  
Energy Gap ◽  
Cholesterol Biosynthesis ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Positive Energy ◽  
Hepatic Expression ◽  
Expression Of Genes

Exercise is a potent facilitator of long-term weight loss maintenance (WLM), whereby it decreases appetite and increases energy expenditure beyond the cost of the exercise bout. We have previously shown that exercise may amplify energy expenditure through energetically expensive nutrient deposition. Therefore, we investigated the effect of exercise on hepatic de novo lipogenesis (DNL) during WLM and relapse to obesity. Obese rats were calorically restricted with (EX) or without (SED) treadmill exercise (1 h/day, 6 days/wk, 15 m/min) to induce and maintain weight loss. After 6 wk of WLM, subsets of WLM-SED and WLM-EX rats were allowed ad libitum access to food for 1 day to promote relapse (REL). An energy gap-matched group of sedentary, relapsing rats (REL-GM) were provided a diet matched to the positive energy imbalance of the REL-EX rats. During relapse, exercise increased enrichment of hepatic DN-derived lipids and induced hepatic molecular adaptations favoring DNL compared with the gap-matched controls. In the liver, compared with both REL-SED and REL-GM rats, REL-EX rats had lower hepatic expression of genes required for cholesterol biosynthesis; greater hepatic expression of genes that mediate very low-density lipoprotein synthesis and secretion; and greater mRNA expression of Cyp27a1, which encodes an enzyme involved in the biosynthesis of bile acids. Altogether, these data provide compelling evidence that the liver has an active role in exercise-mediated potentiation of energy expenditure during early relapse.

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