27 results on '"Lewis GF"'
Search Results
2. Glucagon-like peptide-2 mobilizes lipids from the intestine by a systemic nitric oxide-independent mechanism.
- Author
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Xiao C, Stahel P, Morgantini C, Nahmias A, Dash S, and Lewis GF
- Subjects
- Celiac Artery diagnostic imaging, Chylomicrons chemistry, Chylomicrons metabolism, Humans, Intestinal Mucosa drug effects, Lipoproteins blood, Male, Mesenteric Artery, Superior diagnostic imaging, Middle Aged, Peptides pharmacology, Single-Blind Method, Triglycerides blood, Ultrasonography, Doppler, Glucagon-Like Peptide 2 metabolism, Intestinal Mucosa metabolism, Lipoproteins metabolism, Nitric Oxide metabolism, Triglycerides metabolism
- Abstract
Aim: To test the hypothesis that gut hormone glucagon-like peptide-2 (GLP-2) mobilizes intestinal triglyceride (TG) stores and stimulates chylomicron secretion by a nitric oxide (NO)-dependent mechanism in humans., Methods: In a randomized, single-blind, cross-over study, 10 healthy male volunteers ingested a high-fat formula followed, 7 hours later, by one of three treatments: NO synthase inhibitor L-N
G -monomethyl arginine acetate (L-NMMA) + GLP-2 analogue teduglutide, normal saline + teduglutide, or L-NMMA + placebo. TG in plasma and lipoprotein fractions were measured, along with measurement of blood flow in superior mesenteric and coeliac arteries using Doppler ultrasound in six participants., Results: Teduglutide rapidly increased mesenteric blood flow and TG concentrations in plasma, in TG-rich lipoproteins, and most robustly in chylomicrons. L-NMMA significantly attenuated teduglutide-induced enhancement of mesenteric blood flow but not TG mobilization and chylomicron secretion., Conclusions: GLP-2 mobilization of TG stores and stimulation of chylomicron secretion from the small intestine appears to be independent of systemic NO in humans., (© 2019 John Wiley & Sons Ltd.)- Published
- 2019
- Full Text
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3. Glucose and GLP-2 (Glucagon-Like Peptide-2) Mobilize Intestinal Triglyceride by Distinct Mechanisms.
- Author
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Stahel P, Xiao C, Davis X, Tso P, and Lewis GF
- Subjects
- Animals, Apolipoprotein B-48 analysis, Chylomicrons metabolism, Lymph drug effects, Lymph metabolism, Male, Rats, Rats, Sprague-Dawley, Glucagon-Like Peptide 2 pharmacology, Glucose pharmacology, Intestinal Mucosa metabolism, Triglycerides metabolism
- Abstract
Objective: Dietary triglycerides are partially retained in the intestine within intracellular or extracellular compartments, which can be rapidly mobilized in response to several stimuli, including glucose and GLP-2 (glucagon-like peptide-2). To elucidate the mechanism of intestinal lipid mobilization, this study examined the patterns and time course of lymph flow and triglycerides after glucose and GLP-2 treatment in rats. Approach and Results: Lymph flow, triglyceride concentration, and triglyceride output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal (i.d.) lipid bolus followed 5 hours later by either (1) i.d. saline+intraperitoneal (i.p.) saline (placebo), (2) i.d. glucose plus i.p. saline, (3) i.d. saline+i.p. GLP-2, or (4) i.d. glucose+i.p. GLP-2. GLP-2 and glucose administered alone or in combination stimulated total triglyceride output to a similar extent, but the timing and pattern of stimulation differed markedly. Whereas GLP-2 rapidly increased lymph flow with no effect on lymph triglyceride concentration or triglyceride:apoB48 (apolipoprotein B48) ratio (a surrogate marker of chylomicron size) compared with placebo, glucose transiently decreased lymph flow followed by delayed stimulation of lymph flow and increased lymph triglyceride concentration and triglyceride:apoB48 ratio., Conclusions: Glucose and GLP-2 robustly enhanced intestinal triglyceride output in rats but with different effects on lymph flow, lymph triglyceride concentration, and chylomicron size. GLP-2 stimulated triglyceride output primarily by enhancing lymph flow with no effect on chylomicron size, whereas glucose mobilized intestinal triglycerides, stimulating secretion of larger chylomicrons. This suggests that these 2 stimuli mobilize intestinal lipid by different mechanisms.
- Published
- 2019
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4. Oral Glucose Mobilizes Triglyceride Stores From the Human Intestine.
- Author
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Xiao C, Stahel P, Carreiro AL, Hung YH, Dash S, Bookman I, Buhman KK, and Lewis GF
- Subjects
- Administration, Oral, Adult, Biopsy, Chylomicrons metabolism, Diet, High-Fat, Duodenum pathology, Enterocytes metabolism, Enterocytes ultrastructure, Fasting, Female, Gene Ontology, Humans, Intestinal Mucosa metabolism, Intestinal Mucosa ultrastructure, Lipid Metabolism genetics, Lipoproteins, VLDL metabolism, Male, Middle Aged, Triglycerides blood, Glucose administration & dosage, Intestines chemistry, Triglycerides metabolism
- Abstract
Background & Aims: The small intestine regulates plasma triglyceride (TG) concentration. Within enterocytes, dietary TGs are packaged into chylomicrons (CMs) for secretion or stored temporarily in cytoplasmic lipid droplets (CLDs) until further mobilization. We and others have shown that oral and intravenous glucose enhances CM particle secretion in human beings, however, the mechanisms through which this occurs are incompletely understood., Methods: Two separate cohorts of participants ingested a high-fat liquid meal and, 5 hours later, were assigned randomly to ingest either a glucose solution or an equivalent volume of water. In 1 group (N = 6), plasma and lipoprotein TG responses were assessed in a randomized cross-over study. In a separate group (N = 24), duodenal biopsy specimens were obtained 1 hour after ingestion of glucose or water. Ultrastructural and proteomic analyses were performed on duodenal biopsy specimens., Results: Compared with water, glucose ingestion increased circulating TGs within 30 minutes, mainly in the CM fraction. It decreased the total number of CLDs and the proportion of large-sized CLDs within enterocytes. We identified 2919 proteins in human duodenal tissue, 270 of which are related to lipid metabolism and 134 of which were differentially present in response to glucose compared with water ingestion., Conclusions: Oral glucose mobilizes TGs stored within enterocyte CLDs to provide substrate for CM synthesis and secretion. Future studies elucidating the underlying signaling pathways may provide mechanistic insights that lead to the development of novel therapeutics for the treatment of hypertriglyceridemia., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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5. Recent Advances in Triacylglycerol Mobilization by the Gut.
- Author
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Xiao C, Stahel P, Carreiro AL, Buhman KK, and Lewis GF
- Subjects
- Animals, Dietary Fats metabolism, Enterocytes metabolism, Humans, Intestinal Absorption physiology, Intestinal Mucosa metabolism, Intestine, Small metabolism, Lipid Metabolism physiology, Triglycerides metabolism
- Abstract
Dietary lipid absorption and lipoprotein secretion by the gut are important in maintaining whole-body energy homeostasis and have significant implications for health and disease. The processing of dietary lipids, including storage within and subsequent mobilization and transport from enterocyte cytoplasmic lipid droplets or other intestinal lipid storage pools (including the secretary pathway, lamina propria and lymphatics) and secretion of chylomicrons, involves coordinated steps that are subject to various controls. This review summarizes recent advances in our understanding of the mechanisms that underlie lipid storage and mobilization by small intestinal enterocytes and the intestinal lymphatic vasculature. Therapeutic targeting of lipid processing by the gut may provide opportunities for the treatment and prevention of dyslipidemia, and for improving health status., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
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6. Effects of Intranasal Insulin on Triglyceride-Rich Lipoprotein Particle Production in Healthy Men.
- Author
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Xiao C, Dash S, Stahel P, and Lewis GF
- Subjects
- Administration, Intranasal, Blood Glucose drug effects, Blood Glucose metabolism, Healthy Volunteers, Humans, Infusions, Intravenous, Intestinal Mucosa metabolism, Kinetics, Liver metabolism, Male, Middle Aged, Models, Biological, Ontario, Apolipoprotein B-100 blood, Apolipoprotein B-48 blood, Hypoglycemic Agents administration & dosage, Insulin Lispro administration & dosage, Intestines drug effects, Liver drug effects, Triglycerides blood
- Abstract
Objective: Insulin administered directly into the brain acutely suppresses hepatic glucose production and triglyceride-rich lipoprotein (TRL) secretion in rodents. In addition, intranasally administered insulin, which selectively raises cerebrospinal fluid insulin concentration, suppresses hepatic glucose production in humans; however, its effect on TRL secretion in humans has not previously been examined. In this study, we examined whether intranasal insulin, administered at a dose that has previously been shown to suppress hepatic glucose production, modulates TRL particle secretion by the liver and intestine in humans., Approach and Results: Nine healthy, normolipidemic, and normoglycemic men participated in a study consisting of 2 randomized study arms. Subjects received intranasal lispro insulin (40 IU) or placebo. Because intranasal insulin results in a rapid and transient increase in systemic insulin concentration after administration, we matched systemic insulin concentrations in the 2 study arms by infusing lispro insulin intravenously for 30 minutes together with intranasal placebo administration. Apo (apolipoprotein) B100-containing (hepatically derived) and apoB48-containing (intestinally derived) TRL lipoprotein particle turnover were measured for the ensuing 10 hours under pancreatic clamp conditions and constant fed state, using stable isotope enrichment techniques and multicompartmental modeling. Under these experimental conditions, no significant effects of intranasal insulin versus placebo on TRL apoB100 or B48 concentrations, fractional catabolic rates, or production rates were observed., Conclusions: Insulin delivered intranasally at a dose that has been shown to raise cerebrospinal fluid insulin concentration and suppress hepatic glucose production does not affect TRL particle production by the liver and intestine in healthy men., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03141827., (© 2017 American Heart Association, Inc.)
- Published
- 2017
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7. Novel role of enteral monosaccharides in intestinal lipoprotein production in healthy humans.
- Author
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Xiao C, Dash S, Morgantini C, and Lewis GF
- Subjects
- Adult, Apolipoprotein B-100 metabolism, Apolipoprotein B-48 metabolism, Blood Glucose analysis, Emulsions metabolism, Humans, Male, Middle Aged, Phospholipids metabolism, Soybean Oil metabolism, Fructose metabolism, Glucose metabolism, Intestinal Mucosa metabolism, Lipoproteins biosynthesis, Triglycerides biosynthesis
- Abstract
Objective: Overproduction of triglyceride-rich lipoproteins (TRLs) by liver and intestine contributes to hypertriglyceridemia and may increase cardiovascular risk. Dietary carbohydrates, especially fructose, have been shown to amplify postprandial lipemia but little is known about its effect on intestinal TRL particle production. Here, we examined intestinal and hepatic TRL particle production in response to enteral glucose or fructose in the presence of enteral lipid., Approach and Results: In 2 randomized studies, 4 to 6 weeks apart, 7 healthy male subjects received intraduodenal infusion of Intralipid plus saline or glucose. TRL-apolipoprotein (apo) B48 and apoB100 kinetics were assessed under pancreatic clamp conditions. In a separate study of another 7 subjects under similar conditions, glucose was replaced by fructose. When coinfused with Intralipid into the duodenum, glucose markedly stimulated TRL-apoB48 production (P<0.01), with a concomitant moderate increase in fractional clearance (P<0.05), resulting in net elevation of TRL-apoB48 concentration. TRL-apoB100 concentration, fractional clearance, and production were not significantly affected by glucose. When glucose was replaced by fructose, both TRL-apoB100 and apoB48 production (P<0.05), but not fractional clearance, were enhanced compared with Intralipid alone., Conclusions: These results reveal a novel role of monosaccharides in acutely enhancing intestinal lipoprotein particle production, thereby aggravating hyperlipidemia.
- Published
- 2013
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8. Exenatide, a glucagon-like peptide-1 receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans.
- Author
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Xiao C, Bandsma RH, Dash S, Szeto L, and Lewis GF
- Subjects
- Adult, Apolipoprotein B-100 blood, Apolipoprotein B-48 blood, Blood Glucose metabolism, C-Peptide blood, Down-Regulation, Exenatide, Glucagon blood, Glucagon-Like Peptide-1 Receptor, Humans, Insulin blood, Intestinal Mucosa metabolism, Kinetics, Liver drug effects, Liver metabolism, Male, Models, Biological, Ontario, Postprandial Period, Receptors, Glucagon metabolism, Reference Values, Apolipoproteins B blood, Hypoglycemic Agents administration & dosage, Intestines drug effects, Peptides administration & dosage, Receptors, Glucagon agonists, Triglycerides blood, Venoms administration & dosage
- Abstract
Objective: Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal and hepatic triglyceride-rich lipoprotein production and clearance in healthy humans., Methods and Results: Fifteen normolipidemic, normoglycemic men underwent 2 studies each (SC 10 μg exenatide versus placebo), 4 to 6 weeks apart, in random order, in which triglyceride-rich lipoprotein particle kinetics were examined with a primed, constant infusion of deuterated leucine and analyzed by multicompartmental modeling under pancreatic clamp conditions. A fed state was maintained during each study by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate directly into the duodenum via a nasoduodenal tube. Exenatide significantly suppressed the plasma concentration and production rate of triglyceride-rich lipoprotein-apolipoprotein B-48, but not of triglyceride-rich lipoprotein-apolipoprotein B-100., Conclusions: These results suggest a possible direct effect of exenatide on intestinal lipoprotein particle production, independent of changes in weight gain and satiety as seen in long-term studies and independent of changes in gastric emptying. This finding expands our understanding of the effects of exenatide in metabolic regulation beyond its primary therapeutic role in regulation of glucose homeostasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov, NCT01056549.
- Published
- 2012
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9. Gut-liver interaction in triglyceride-rich lipoprotein metabolism.
- Author
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Xiao C, Hsieh J, Adeli K, and Lewis GF
- Subjects
- Animals, Apolipoproteins B metabolism, Humans, Intestinal Mucosa metabolism, Lipoproteins metabolism, Liver metabolism, Triglycerides metabolism
- Abstract
The liver and intestine have complementary and coordinated roles in lipoprotein metabolism. Despite their highly specialized functions, assembly and secretion of triglyceride-rich lipoproteins (TRL; apoB-100-containing VLDL in the liver and apoB-48-containing chylomicrons in the intestine) are regulated by many of the same hormonal, inflammatory, nutritional, and metabolic factors. Furthermore, lipoprotein metabolism in these two organs may be affected in a similar fashion by certain disorders. In insulin resistance, for example, overproduction of TRL by both liver and intestine is a prominent component of and underlies other features of a complex dyslipidemia and increased risk of atherosclerosis. The intestine is gaining increasing recognition for its importance in affecting whole body lipid homeostasis, in part through its interaction with the liver. This review aims to integrate recent advances in our understanding of these processes and attempts to provide insight into the factors that coordinate lipid homeostasis in these two organs in health and disease.
- Published
- 2011
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10. Adding monounsaturated fatty acids to a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia.
- Author
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Jenkins DJ, Chiavaroli L, Wong JM, Kendall C, Lewis GF, Vidgen E, Connelly PW, Leiter LA, Josse RG, and Lamarche B
- Subjects
- Adult, Aged, Cardiovascular Diseases prevention & control, Female, Follow-Up Studies, Food, Humans, Hypercholesterolemia blood, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Cholesterol, HDL blood, Cholesterol, LDL blood, Fatty Acids, Monounsaturated therapeutic use, Hypercholesterolemia diet therapy, Triglycerides blood
- Abstract
Background: Higher intake of monounsaturated fat may raise high-density lipoprotein (HDL) cholesterol without raising low-density lipoprotein (LDL) cholesterol. We tested whether increasing the monounsaturated fat content of a diet proven effective for lowering LDL cholesterol (dietary portfolio) also modified other risk factors for cardiovascular disease, specifically by increasing HDL cholesterol, lowering serum triglyceride and further reducing the ratio of total to HDL cholesterol., Methods: Twenty-four patients with hyperlipidemia consumed a therapeutic diet very low in saturated fat for one month and were then randomly assigned to a dietary portfolio low or high in monounsaturated fatty acid for another month. We supplied participants' food for the two-month period. Calorie intake was based on Harris-Benedict estimates for energy requirements., Results: For patients who consumed the dietary portfolio high in monounsaturated fat, HDL cholesterol rose, whereas for those consuming the dietary portfolio low in monounsaturated fat, HDL cholesterol did not change. The 12.5% treatment difference was significant (0.12 mmol/L, 95% confidence interval [CI] 0.05 to 0.21, p = 0.003). The ratio of total to HDL cholesterol was reduced by 6.5% with the diet high in monounsaturated fat relative to the diet low in monounsaturated fat (-0.28, 95% CI -0.59 to -0.04, p = 0.025). Patients consuming the diet high in monounsaturated fat also had significantly higher concentrations of apolipoprotein AI, and their C-reactive protein was significantly lower. No treatment differences were seen for triglycerides, other lipids or body weight, and mean weight loss was similar for the diets high in monounsaturated fat (-0.8 kg) and low in monounsaturated fat (-1.2 kg)., Interpretation: Monounsaturated fat increased the effectiveness of a cholesterol-lowering dietary portfolio, despite statin-like reductions in LDL cholesterol. The potential benefits for cardiovascular risk were achieved through increases in HDL cholesterol, further reductions in the ratio of total to HDL cholesterol and reductions in C-reactive protein. (ClinicalTrials.gov trial register no. NCT00430430.).
- Published
- 2010
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11. Triglyceride-rich lipoprotein-associated apolipoprotein C-III production is stimulated by plasma free fatty acids in humans.
- Author
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Pavlic M, Valéro R, Duez H, Xiao C, Szeto L, Patterson BW, and Lewis GF
- Subjects
- Adult, Fat Emulsions, Intravenous administration & dosage, Glycerol metabolism, Heparin metabolism, Humans, Infusions, Intravenous, Lipoproteins, HDL blood, Male, Middle Aged, Postprandial Period, Random Allocation, Up-Regulation, Apolipoprotein C-III blood, Fat Emulsions, Intravenous pharmacokinetics, Fatty Acids, Nonesterified blood, Lipolysis, Triglycerides blood
- Abstract
Objective: Insulin resistant states are associated with increased fatty acid flux to liver and intestine, which stimulates the production of triglyceride-rich lipoproteins (TRL). ApoC-III production and plasma and TRL concentrations are increased in insulin resistance and may contribute to the hypertriglyceridemia of these conditions. The mechanism underlying that increase is not known, but because apoC-III and VLDL production are closely linked we hypothesized that FFAs may stimulate TRL apoC-III production., Methods and Results: We used Intralipid/heparin (IH) to raise plasma FFA in 12 healthy men in the fed state, and stable isotopes to examine apoC-III metabolism. TRL apoC-III concentration was significantly higher in the IH study, and this increase was associated with higher production (PR) and fractional catabolic rate (FCR). The increase in production was greater than in FCR (90% versus 30%, respectively), accounting for the elevated concentration. Glycerol infusion had no effect on apoC-III concentration, PR, or FCR compared to saline, indicating that the effect was not attributable to glycerol released from intralipid., Conclusions: These findings confirm that TRL apoC-III production is stimulated by an acute elevation of plasma FFAs, suggesting a novel regulatory pathway that may play a role in the overproduction of TRL apoC-III in insulin resistant states.
- Published
- 2008
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12. Enhanced cellular uptake of remnant high-density lipoprotein particles: a mechanism for high-density lipoprotein lowering in insulin resistance and hypertriglyceridemia.
- Author
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Xiao C, Watanabe T, Zhang Y, Trigatti B, Szeto L, Connelly PW, Marcovina S, Vaisar T, Heinecke JW, and Lewis GF
- Subjects
- Anticoagulants pharmacology, Apolipoprotein A-I metabolism, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Cell Line, Cell Line, Tumor, Cholesterol, VLDL metabolism, Heparin pharmacology, Humans, Hypertriglyceridemia pathology, Kidney cytology, Kidney drug effects, Lipase metabolism, Liver drug effects, Liver pathology, Liver Neoplasms metabolism, Liver Neoplasms pathology, Scavenger Receptors, Class B metabolism, Cholesterol, HDL metabolism, Hypertriglyceridemia metabolism, Insulin Resistance physiology, Kidney metabolism, Lipoproteins, HDL metabolism, Liver metabolism, Triglycerides metabolism
- Abstract
A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. The increased binding of remnant HDL was not mediated by the low-density lipoprotein receptor or scavenger receptor class B type I (SR-BI), because enhanced remnant HDL binding was observed in low-density lipoprotein receptor-deficient cells with or without SR-BI overexpression. Disruption of cell surface heparan sulfate proteoglycans or blockage of apolipoprotein E-mediated lipoprotein binding also did not abolish the enhanced remnant HDL binding. Our observations indicate that remodeling of triglyceride-enriched HDL by hepatic lipase may result in enhanced binding, internalization, and degradation in tissues involved in HDL catabolism, contributing to rapid clearance and overall lowering of plasma HDL cholesterol in insulin resistance and hypertriglyceridemia.
- Published
- 2008
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13. Dissociation between the insulin-sensitizing effect of rosiglitazone and its effect on hepatic and intestinal lipoprotein production.
- Author
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Duez H, Lamarche B, Uffelman KD, Valéro R, Szeto L, Lemieux S, Cohn JS, and Lewis GF
- Subjects
- Adult, Apolipoprotein B-100 biosynthesis, Apolipoprotein B-48 biosynthesis, Cross-Over Studies, Fatty Acids, Nonesterified blood, Humans, Male, Middle Aged, Rosiglitazone, Hypoglycemic Agents pharmacology, Insulin blood, Intestinal Mucosa metabolism, Lipoproteins biosynthesis, Liver metabolism, Thiazolidinediones pharmacology, Triglycerides biosynthesis
- Abstract
Context: Despite its potent, well-documented insulin-sensitizing effects, rosiglitazone (RSG) does not effectively ameliorate the hypertriglyceridemia of insulin-resistant or diabetic individuals and has even been shown to slightly but significantly increase triglyceride-rich lipoproteins (TRL) in some studies. The mechanism of this effect is currently not known., Objective: We investigated the effect of RSG treatment on TRL metabolism., Design: This was a 12-wk, single-sequence, cross-over study of rosiglitazone vs. placebo for 6 wk., Participants: Participants included 17 nondiabetic men with a broad range of insulin sensitivity., Intervention: INTERVENTION included rosiglitazone 8 mg/d vs. placebo for 6 wk., Main Outcome Measure: TRL metabolism (concentration, production and catabolic rates) was assessed in a constant fed state with a 12-h primed constant infusion of [D3]l-leucine and multicompartmental modeling., Results: RSG treatment resulted in significant insulin sensitization with no change in body weight. Fasting plasma triglyceride (TG) concentration, however, was higher with RSG vs. placebo (P = 0.0006), as were fasting and fed TRL-TG, TRL-apoB-48, and TRL-apoB-100 (fed TRL-apoB-48: 0.93 +/- 0.08 vs. 0.76 +/- 0.07 mg/dl, P =0.017, and fed TRL-apoB-100: 15.57 +/- 0.90 vs. 13.71 +/- 1.27 mg/dl, P = 0.029). This small but significant increase in plasma TRL concentration was explained by a tendency for RSG to increase TRL production and reduce particle clearance, as indicated by the significantly increased production to clearance ratios for both apoB-48-containing (0.43 +/- 0.03 vs. 0.34 +/- 0.03, P = 0.048) and apoB-100-containing (7.0 +/- 0.4 vs. 6.2 +/- 0.6, P = 0.029) TRL., Conclusion: These data indicate dissociation between the insulin-sensitizing effects of RSG and absence of anticipated reductions in production rates of apoB-100- and apoB-48-containing-TRL particles, which may explain the absence of TG lowering seen in humans treated with this agent.
- Published
- 2008
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14. Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I.
- Author
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Rashid S, Trinh DK, Uffelman KD, Cohn JS, Rader DJ, and Lewis GF
- Subjects
- Adenoviridae genetics, Adult, Animals, Cells, Cultured, Disease Models, Animal, Gene Transfer Techniques, Humans, Hypertriglyceridemia blood, Hypertriglyceridemia chemically induced, Kinetics, Lipase deficiency, Lipids blood, Lipoproteins, HDL chemistry, Lipoproteins, HDL metabolism, Lipoproteins, VLDL chemistry, Male, Rabbits, Apolipoprotein A-I pharmacokinetics, Lipase biosynthesis, Lipoproteins, HDL pharmacokinetics, Liver enzymology, Triglycerides metabolism
- Abstract
Background: We have shown previously that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, contributes to HDL lowering in humans by enhancing the clearance of HDL apolipoprotein (apo) A-I from the circulation. In the New Zealand White rabbit, an animal naturally deficient in hepatic lipase (HL), we demonstrated that TG enrichment of HDL per se is not sufficient to enhance HDL clearance in the absence of ex vivo lipolysis by HL. Here, we examined in the rabbit the interaction between in vivo HL lipolytic action and HDL TG enrichment on the subsequent metabolic clearance of HDL apoA-I., Methods and Results: The clearance of HDL, TG-enriched with human VLDL (12% mass TG), was compared with a simultaneously injected native rabbit HDL tracer (8% TG) 5 to 7 days after injection of recombinant (r) adenovirus expressing either the human HL or lacZ transgene (n=6 animals each). In rHL-Adv rabbits, HL activity levels were 2- to 7-fold higher (versus rlacZ-Adv controls; P<0.01), and there were significant (P<0.05) reductions in HDL TG (-18%), cholesterol (-21%), cholesteryl ester (-24%), and phospholipid (-14%). Moreover, the clearance of TG-enriched versus native HDL was significantly greater (by 50%; 0.122+/-0.022 versus 0.081+/-0.015 pools/h; P<0.01) in rHL-Adv rabbits but not in controls., Conclusions: These studies have shown that TG enrichment of HDL in the presence but not in the absence of in vivo expression of moderate levels of lipolytically active HL results in enhanced HDL clearance, demonstrating the important interaction between TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.
- Published
- 2003
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15. Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction.
- Author
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Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF, and Adeli K
- Subjects
- Acetates metabolism, Animals, Apolipoprotein B-48, Apolipoproteins B biosynthesis, Cells, Cultured, Cricetinae, Epithelial Cells cytology, Epithelial Cells physiology, Intestine, Small, Kinetics, Male, Mesocricetus, Models, Animal, Polyethylene Glycols pharmacology, Surface-Active Agents pharmacology, Time Factors, Tritium, Fasting physiology, Fructose pharmacology, Hepatocytes metabolism, Insulin Resistance physiology, Intestinal Mucosa metabolism, Lipoproteins biosynthesis, Postprandial Period physiology, Triglycerides biosynthesis
- Abstract
Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.
- Published
- 2002
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16. Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster.
- Author
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Carpentier A, Taghibiglou C, Leung N, Szeto L, Van Iderstine SC, Uffelman KD, Buckingham R, Adeli K, and Lewis GF
- Subjects
- Animal Nutritional Physiological Phenomena, Animals, Apolipoproteins B metabolism, Cricetinae, Fructose metabolism, Hepatocytes metabolism, Hypoglycemic Agents pharmacology, Immunoblotting, Insulin metabolism, Insulin Receptor Substrate Proteins, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Liver cytology, Male, Mesocricetus, Perfusion, Phosphoproteins metabolism, Phosphorylation, Rosiglitazone, Signal Transduction, Thiazoles pharmacology, Time Factors, Fructose pharmacology, Lipoproteins, VLDL metabolism, Liver metabolism, Microsomes, Liver metabolism, Thiazolidinediones, Triglycerides metabolism
- Abstract
To determine whether reduction of insulin resistance could ameliorate fructose-induced very low density lipoprotein (VLDL) oversecretion and to explore the mechanism of this effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted insulin-mediated suppression of the glucose production rate and to a approximately 2-fold increase in whole body insulin-mediated glucose disappearance rate (p < 0.001). Rosiglitazone ameliorated the defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine phosphatase 1B levels were increased with fructose feeding and were markedly reduced by rosiglitazone. Rosiglitazone treatment led to a approximately 50% reduction of VLDL secretion rates (p < 0.05) in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR (fructose-fed + rosiglitazone-treated) versus F (fructose-fed + placebo-treated) hamsters, although there was a trend toward a lower clearance with rosiglitazone. Enhanced stability of nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was evident, and rosiglitazone treatment resulted in a significant reduction in apoB stability. The increase in intracellular mass of microsomal triglyceride transfer protein seen with fructose feeding was reduced by treatment with rosiglitazone. In conclusion, improvement of hepatic insulin signaling with rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, is associated with reduced hepatic VLDL assembly and secretion due to reduced intracellular apoB stability.
- Published
- 2002
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17. Sensitivity to acute insulin-mediated suppression of plasma free fatty acids is not a determinant of fasting VLDL triglyceride secretion in healthy humans.
- Author
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Carpentier A, Patterson BW, Leung N, and Lewis GF
- Subjects
- Adolescent, Adult, Apolipoproteins B blood, Body Mass Index, C-Peptide blood, Deuterium, Female, Glucose Tolerance Test, Glycerol, Humans, Insulin administration & dosage, Insulin blood, Insulin Resistance, Male, Metabolic Clearance Rate, Fasting, Fatty Acids, Nonesterified blood, Insulin pharmacology, Lipoproteins, VLDL blood, Triglycerides blood
- Abstract
One important mechanism whereby obesity-associated insulin resistance leads to VLDL overproduction is thought to be by the increased flux of free fatty acids (FFAs) from extrahepatic tissues to liver, which arises as a direct consequence of impaired insulin action in adipose tissue and skeletal muscle. The aim of the present study was to address whether direct measures of peripheral tissue insulin sensitivity with regard to FFAs and glucose in the fasting state are good predictors of postabsorptive VLDL triglyceride secretion rate (VLDL-TG ASR) in humans, independent of obesity. Eighteen healthy control subjects, after an overnight fast, underwent three studies 3 weeks apart, in random order. Study 1: VLDL-TG levels, fractional clearance rate (per h), and VLDL-TG ASR were determined after an intravenous bolus of [1,1,2,3,3-(2)H(5)] glycerol. Study 2: Insulin sensitivity (S(I)), acute insulin response (AIR), and acute C-peptide response to glucose were assessed by frequently sampled intravenous glucose tolerance test using the minimal model approach. Study 3: Insulin-mediated suppression of plasma FFAs (k) and insulin clearance were assessed in response to a low-dose stepwise intravenous insulin infusion. BMI (R(2) = 0.54), AIR, and fasting insulin levels were positively and S(I) negatively correlated with VLDL-TG ASR, but there was no significant association with plasma FFAs or k. Only BMI remained significantly associated with VLDL-TG ASR in multivariate analysis. The best multivariate model for VLDL-TG ASR (R(2) = 0.61, P = 0.0008) included BMI (P = 0.0008) and S(I) (P = 0.12, inversely correlated). VLDL-TG secretion is predicted by BMI, independently of direct measures of insulin sensitivity. The sensitivity to insulin's acute suppressive effect on plasma FFA levels during fasting is not an important determinant of postabsorptive VLDL-TG secretion in humans.
- Published
- 2002
- Full Text
- View/download PDF
18. Lipolytically modified triglyceride-enriched HDLs are rapidly cleared from the circulation.
- Author
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Rashid S, Barrett PH, Uffelman KD, Watanabe T, Adeli K, and Lewis GF
- Subjects
- Animals, Apolipoprotein A-I blood, Hypertriglyceridemia metabolism, Kinetics, Lipase metabolism, Lipolysis, Lipoproteins, HDL chemistry, Liver enzymology, Male, Rabbits, Triglycerides analysis, Hypertriglyceridemia blood, Lipoproteins, HDL blood, Lipoproteins, HDL metabolism, Triglycerides metabolism
- Abstract
The precise biochemical mechanisms underlying the reduction of HDL levels in hypertriglyceridemic states are currently not known. In humans, we showed that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, enhances the clearance of HDL-associated apolipoprotein A-I (apoA-I) from the circulation. In the New Zealand White rabbit (an animal model naturally deficient in hepatic lipase [HL]), however, TG enrichment of HDL is not sufficient to alter the clearance of either the protein or lipid moieties of HDL. In the present study, therefore, we determined in the New Zealand White rabbit the combined effects of ex vivo TG enrichment and lipolytic transformation of HDL by HL on the subsequent metabolic clearance of HDL apoA-I. Results of the in vivo kinetic studies (n=18 animals) showed that apoA-I associated with TG-enriched rabbit HDL modified ex vivo by catalytically active HL was cleared 22% more rapidly versus TG-enriched HDL incubated with heat-inactivated HL, and 26% more rapidly than fasting (TG-poor) HDL incubated with active HL (P<0.05 for both). Furthermore, a strong correlation was observed between the HDL TG content and apoA-I fractional catabolic rate (0.59, P<0.05) in the combined active HL groups. These data establish that TG enrichment of HDL with subsequent lipolysis by HL enhances HDL apoA-I clearance, but neither TG enrichment of HDL without HL lipolysis nor HL lipolysis in the absence of previous TG enrichment of HDL is sufficient to enhance HDL clearance. These data further support the important interaction between HDL TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.
- Published
- 2002
- Full Text
- View/download PDF
19. Triglyceride enrichment of HDL does not alter HDL-selective cholesteryl ester clearance in rabbits.
- Author
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Rashid S, Uffelman KD, Barrett PH, Vicini P, Adeli K, and Lewis GF
- Subjects
- Animals, Kinetics, Lipase metabolism, Liver enzymology, Male, Rabbits, Cholesterol Esters metabolism, Lipoproteins, HDL blood, Triglycerides blood
- Abstract
Triglyceride (TG) enrichment of high density lipoprotein (HDL), which occurs in hypertriglyceridemic states, significantly enhances the rate at which HDL apolipoprotein (apo)A-I is cleared from the circulation of healthy humans. In the New Zealand White (NZW) rabbit, a species naturally deficient in hepatic lipase (HL), TG enrichment of HDL requires prior lipolytic modification to enhance apoA-I clearance. However, the effect of TG enrichment of HDL on the subsequent clearance of HDL cholesteryl ester (CE) has not previously been examined in vivo. Therefore, we investigated, in the NZW rabbit, the effect of ex vivo TG enrichment of rabbit HDL (by incubation with human very low density lipoprotein) on the clearance of HDL CE and apoA-I radiolabeled with (3)H-cholesteryl oleyl ether and with (131)I, respectively. In nine experiments, TG enrichment of rabbit HDL resulted in an 87% average increase in HDL TG and a corresponding 31% reduction in HDL CE content. The calculated apoA-I and CE fractional catabolic rates associated with TG-rich versus fasting HDL tracers were not significantly different (apoA-I: 0.119 +/- 0.017 vs. 0.107 +/- 0.024 pools per h, P = 0.68; CE: 0.147 +/- 0.014 vs. 0.114 +/- 0.019 pools per h, P = 0.20). In an animal model deficient in HL, TG enrichment of HDL did not alter the rates of HDL apoA-I or selective CE clearance. Further studies are needed to determine whether, in the presence of HL, TG enrichment of HDL alters selective HDL CE clearance.
- Published
- 2001
20. A stable isotope method using a [(2)H(5)]glycerol bolus to measure very low density lipoprotein triglyceride kinetics in humans.
- Author
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Lemieux S, Patterson BW, Carpentier A, Lewis GF, and Steiner G
- Subjects
- Acetates administration & dosage, Adult, Body Mass Index, Carbon Isotopes, Deuterium pharmacokinetics, Glycerol administration & dosage, Glycerol pharmacokinetics, Humans, Kinetics, Lipids blood, Male, Scintillation Counting, Tritium administration & dosage, Tritium pharmacokinetics, Deuterium administration & dosage, Glycerol metabolism, Isotope Labeling methods, Lipoproteins, VLDL metabolism, Triglycerides metabolism
- Abstract
We have developed a method using a bolus of [(2)H(5)]glycerol to determine parameters of VLDL-triglyceride (VLDL-TG) turnover and have compared the data to that obtained using simultaneously a bolus of [2-(3)H]glycerol in six young normolipidemic men. No measurable enrichment was found after 12 h for [(2)H(5)]glycerol; therefore, we could only perform a monoexponential analysis of its data. No differences in fractional catabolic rate (FCR) were seen when comparing the multicompartmental modeling of [2-(3)H]glycerol data (modeled over 48 h) either to the monoexponential analyses of the [2-(3)H]glycerol or that of the [(2)H(5)]glycerol data. The two monoexponential approaches were highly correlated (r = 0.96 for FCR), however, FCR was 18% higher with the [(2)H(5)]glycerol than with the [2-(3)H]glycerol data (P < 0.003). In all six subjects, a 10-h infusion of [1-(13)C]acetate was started at the same time as the glycerol boluses were given. In two men we were able reliably to detect VLDL-TG-fatty acid enrichment. The measurement of FCR in these two subjects using the mass isotopomer distribution analysis (MIDA) approach was in good agreement (within 10%) with FCRs determined with the labeled glycerol methods. In conclusion, our results have shown that results obtained with the [(2)H(5)]glycerol bolus were highly correlated with those obtained with the [2-(3)H]glycerol, but the FCRs were slightly higher with the former. We have also demonstrated that FCRs determined from monoexponential modeling were in good agreement with those determined from the multicompartmental modeling of the TG-glycerol data.
- Published
- 1999
21. Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.
- Author
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Lamarche B, Uffelman KD, Carpentier A, Cohn JS, Steiner G, Barrett PH, and Lewis GF
- Subjects
- Adult, Humans, Lipid Metabolism, Lysophosphatidylcholines metabolism, Male, Phosphatidylcholines metabolism, Proteins metabolism, Sphingomyelins metabolism, Apolipoprotein A-I metabolism, Lipoproteins, HDL metabolism, Triglycerides metabolism
- Abstract
Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plasma of six normolipidemic men (mean age: 29.7 +/- 2.7 years) in the fasting state and after a five-hour intravenous infusion with a synthetic TG emulsion, Intralipid. Intralipid infusion resulted in a 2.1-fold increase in the TG content of HDL. Each tracer was then whole-labeled with 125I or 131I and injected intravenously into the subject. Apo A-I in TG-enriched HDL was cleared 26% more rapidly than apo A-I in fasting HDL. A strong correlation between the Intralipid-induced increase in the TG content of HDL and the increase in HDL apo A-I fractional catabolic rate reinforced the importance of TG enrichment of HDL in enhancing its metabolic clearance. HDL was separated further into lipoproteins containing apo A-II (LpAI:AII) and those without apo A-II (LpAI). Results revealed that the enhanced clearance of apo A-I from TG-enriched HDL could be largely attributed to differences in the clearance of LpAI but not LpAI:AII. This is, to our knowledge, the first direct demonstration in humans that TG enrichment of HDL enhances the clearance of HDL apo A-I from the circulation. This phenomenon could provide an important mechanism explaining how HDL apo A-I and HDL cholesterol are lowered in hypertriglyceridemic states.
- Published
- 1999
- Full Text
- View/download PDF
22. Atherosclerosis prevention for the next decade: risk assessment beyond low density lipoprotein cholesterol.
- Author
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Lamarche B and Lewis GF
- Subjects
- Arteriosclerosis blood, Cholesterol, HDL blood, Cholesterol, LDL blood, Female, Humans, Hyperlipidemias complications, Male, Risk Factors, Arteriosclerosis prevention & control, Hypercholesterolemia complications, Triglycerides blood
- Abstract
Several lines of evidence have demonstrated that increased plasma cholesterol plays a primary role in the etiology of atherosclerosis and ischemic heart disease (IHD). Our ability to manage IHD adequately based on plasma cholesterol or low density lipoprotein (LDL) cholesterol concentrations is challenged, however, by evidence suggesting that a significant proportion of individuals with IHD or who will eventually develop IHD have desirable cholesterol concentrations. These observations have generated much interest in the scientific community, with the resultant identification of new metabolic risk factors that may help, in the future, to improve our ability to reduce the risk of IHD adequately. This review presents evidence that hypertriglyceridemia, particularly when associated with reduced high density lipoprotein (HDL) cholesterol concentrations and abdominal or visceral obesity, is a highly atherogenic phenotype, one that requires aggressive risk reduction management. Hypertriglyceridemia is frequently associated with elevated plasma apolipoprotein B concentrations, with states of hyperinsulinemia or insulin resistance and with small, dense LDL particles, which may all contribute to increase the risk of IHD further. This evidence suggests that a therapeutic strategy based on the assessment of plasma triglyceride concentrations, along with HDL cholesterol levels and abdominal obesity, may be a cost effective approach to assessing the high atherogenic risk of visceral obesity and insulin resistance. We can no longer afford to focus our attention exclusively on the detection and management of elevated LDL cholesterol concentrations, and need to adopt comprehensive risk reduction strategies in order to lower the incidence of IHD.
- Published
- 1998
23. Analysis of particle size and lipid composition as determinants of the metabolic clearance of human high density lipoproteins in a rabbit model.
- Author
-
Lamarche B, Uffelman KD, Steiner G, Barrett PH, and Lewis GF
- Subjects
- Adult, Aged, Animals, Apolipoprotein A-I blood, Apolipoprotein A-II blood, Blood Proteins metabolism, Cholesterol blood, Cholesterol Esters blood, Chromatography, Gel, Fasting, Fatty Acids, Nonesterified blood, Humans, Kinetics, Lipase metabolism, Lipoproteins, HDL isolation & purification, Liver enzymology, Metabolic Clearance Rate, Middle Aged, Phospholipids blood, Rabbits, Lipoproteins, HDL blood, Lipoproteins, HDL pharmacokinetics, Triglycerides blood
- Abstract
Hypertriglyceridemia is commonly associated with triglyceride (TG) enrichment of high density lipoprotein (HDL) and reduction in HDL cholesterol and apolipoprotein A-I levels. We have recently reported that lipolytic modification of TG-rich HDL, which reduces particle size, enhances its clearance from the circulation. In the present study, we examined the role of particle size and lipid composition in determining the metabolic clearance of human HDL, in the absence of substantial in vivo modification of the particle by hepatic lipase. The rabbit, which has a very low hepatic lipase activity, was used for this purpose. Plasma fractions d < 1.21 g/ml were first isolated by ultracentrifugation from fasting humans with normal (NTG, n=6, mean plasma TG concentration=1.26+/-0.21 (SEM) mmol/l) or elevated plasma TG levels (HTG, n=5, TG=4.49+/-0.65 mmol/l). Small and large HDL particles were separated by gel filtration chromatography and were labeled with either 125I or (131)I. Large HDL were cleared more rapidly than small HDL in 10 out of 11 studies (P=0.006). There was, however, no difference in the fractional catabolic rate (FCR) of large HDL isolated from NTG versus from HTG subjects or in the FCR of small HDL from NTG versus HTG individuals. There was also no correlation between the TG content of HDL and its FCR. In summary, large, lipid-rich human high density lipoproteins (HDL) are cleared more rapidly than small human HDL in rabbits. These results, combined with our previous observation, also support the hypothesis that triglyceride enrichment of HDL, in the absence of substantial lipolytic modification, is not sufficient to enhance its clearance from the circulation.
- Published
- 1998
24. Important contribution of lipoprotein particle number to plasma triglyceride concentration in type 2 diabetes.
- Author
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Steiner G, Tkác I, Uffelman KD, and Lewis GF
- Subjects
- Adult, Aged, Apolipoproteins B blood, Data Interpretation, Statistical, Female, Humans, Male, Middle Aged, Subcellular Fractions chemistry, Diabetes Mellitus, Type 2 blood, Lipoproteins blood, Triglycerides blood
- Abstract
The aim of the present study was to determine the contributions of particle size versus number to differences in plasma triglyceride-rich lipoprotein concentrations in patients with type 2 diabetes. Fasting plasma was obtained from 174 consecutive eligible men and women with type 2 diabetes (with or without insulin treatment, mean age 57.0 + 6.3 years) who were undergoing coronary angiography. The triglyceride-rich (Sf 12-400) lipoproteins (TRL) were subfractionated into the Sf 12-60 and Sf 60-400 subfractions. Particle numbers, estimated by measuring apolipoprotein B by electroimmunoassay, in each of these lipoprotein fractions were related to enzymatically determined triglyceride levels in the triglyceride-rich lipoproteins. Approximately 87% of the triglyceride-rich lipoprotein particles were in the Sf 12-60 fraction and 13% in the Sf 60-400 fraction. Multiple linear regression indicated that 69% (i.e. r2=0.69) of the variance in the triglyceride levels could by explained by differences in TRL particle number and 17% (i. e. r2=0.17) by the differences in particle triglyceride content. These observations are similar in each gender and in those with or without insulin treatment. In conclusion, in type 2 diabetes, the vast majority of triglyceride-rich lipoproteins are smaller particles which are in the Sf 12-60 fraction. Differences in particle number, rather than triglyceride content, account for approximately 70% of the differences in triglyceride levels observed between individuals. Previous demonstrations, in those without diabetes, of an association between small triglyceride-rich lipoproteins with coronary artery disease suggest the importance of these findings to the increased atherosclerosis in diabetes.
- Published
- 1998
- Full Text
- View/download PDF
25. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals.
- Author
-
Lewis GF, Uffelman KD, Szeto LW, and Steiner G
- Subjects
- Acute Disease, Adult, Apolipoproteins B blood, Blood Glucose analysis, Fatty Acids, Nonesterified blood, Female, Glucose Clamp Technique, Humans, Insulin Resistance physiology, Iodine Radioisotopes, Lipoproteins, VLDL blood, Middle Aged, Tritium, Apolipoproteins B biosynthesis, Hyperinsulinism blood, Lipoproteins, VLDL biosynthesis, Obesity blood, Triglycerides blood
- Abstract
The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU.m-2 x min-1) in 17 women (8 chronically hyperinsulinemic obese, BMI = 35.7 kg/m2; 9 normal weight, BMI = 22.5 kg/m2). During acute hyperinsulinemia, plasma FFA decreased by approximately 95% within 1 h in both groups. VLDL triglyceride production decreased 66% in the control subjects (P = 0.0003) and 67% in obese subjects (P = 0.0003). ApoB production decreased 53% in control subjects (P = 0.03) but only 8% in obese (NS). Plasma triglycerides decreased by 40% from baseline in control subjects (P < 0.0001) but only by 10% in obese subjects (P = NS). Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia (P = 0.003). In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably. Acute hyperinsulinemia in humans: 1) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects. Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism.
- Published
- 1993
- Full Text
- View/download PDF
26. Role of basal triglyceride and high density lipoprotein in determination of postprandial lipid and lipoprotein responses.
- Author
-
O'Meara NM, Lewis GF, Cabana VG, Iverius PH, Getz GS, and Polonsky KS
- Subjects
- Blood Glucose analysis, Diterpenes, Fasting, Fatty Acids, Nonesterified blood, Humans, Insulin blood, Lipoproteins, HDL blood, Male, Retinyl Esters, Vitamin A analogs & derivatives, Vitamin A blood, Eating, Lipids blood, Lipoproteins blood, Lipoproteins, HDL physiology, Triglycerides physiology
- Abstract
The present study reports on the interaction between basal triglyceride and high density lipoprotein (HDL) cholesterol in determining the magnitude of postprandial triglyceridemia. The vitamin A fat-loading test was used to label intestinally derived triglyceride-rich particles after a high fat meal in 18 subjects with low HDL cholesterol and 6 control subjects who had normal fasting triglyceride and HDL cholesterol levels. The patients with low HDL cholesterol were divided into 2 groups on the basis of their basal triglyceride concentrations; 11 had normal triglyceride levels, and 7 had elevated serum triglycerides (HTG). In the HTG-low HDL group, the incremental area under the triglyceride curve was significantly greater (P less than 0.0003) than that in the other 2 groups, between whom no significant differences in triglyceride response were observed. Retinyl palmitate levels measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction were also significantly greater in low HDL subjects with HTG, while the concentrations in low HDL subjects with normal triglyceride levels and control subjects were similar. Although basal HDL cholesterol levels in all study subjects were negatively correlated with the area under the incremental triglyceride curve (r = -0.42; P less than 0.05), this correlation was weak, in contrast to the correlation between fasting triglyceride levels and incremental triglyceride area (r = 0.56; P less than 0.005). Furthermore, basal HDL cholesterol levels did not correlate with the area under the chylomicron or nonchylomicron curves, whereas basal triglyceride levels were significantly correlated (P = 0.0001) with both of these variables. The HDL particles of both low HDL groups had a significantly higher proportion of triglyceride compared to the HDL particles in the control subjects. In conclusion, 1) fasting triglyceride levels are a more powerful indicator of the postprandial lipid response than basal HDL cholesterol in subjects with low HDL cholesterol levels; 2) patients with low HDL cholesterol levels do not preferentially accumulate chylomicron remnants after a meal unless they have coexisting hypertriglyceridemia; and 3) abnormalities in the levels of triglyceride-rich particles post-prandially are unlikely to be responsible for the increased incidence of atherosclerosis in low HDL patients who are normotriglyceridemic.
- Published
- 1992
- Full Text
- View/download PDF
27. Postprandial triglyceride response in type 1 (insulin-dependent) diabetes mellitus is not altered by short-term deterioration in glycaemic control or level of postprandial insulin replacement.
- Author
-
Lewis GF, O'Meara NM, Cabana VG, Blackman JD, Pugh WL, Druetzler AF, Lukens JR, Getz GS, and Polonsky KS
- Subjects
- Adult, Blood Glucose metabolism, Cholesterol blood, Cholesterol, HDL blood, Diabetes Mellitus, Type 1 drug therapy, Fatty Acids, Nonesterified blood, Female, Humans, Insulin blood, Kinetics, Male, Diabetes Mellitus, Type 1 blood, Eating, Insulin therapeutic use, Triglycerides blood
- Abstract
Unlabelled: The effect of deteriorating glycaemic control on the lipoprotein responses to the ingestion of a high fat meal was investigated in seven normolipidaemic Type 1 (insulin-dependent) diabetic patients and the results were compared with corresponding responses in seven normolipidaemic control subjects. In addition, the importance of insulin in regulating the postprandial lipoprotein responses was examined by comparing the results obtained from the diabetic patients maintained on a basal infusion of insulin throughout the study with those obtained when a step-up, step-down insulin infusion was administered following the meal. Vitamin A was added to the test meal in all subjects to trace the metabolism of the chylomicron (Sf greater than 1000) and non-chylomicron (Sf less than 1000) fractions in the postprandial period. No differences in fasting and postprandial triglyceride levels nor in the concentration of the chylomicron and non-chylomicron fractions were observed between diabetic and control subjects. In the diabetic patients short-term (two-week) deterioration in glycaemic control did not have any adverse influence on the basal and postprandial lipid responses. However, while the amount of insulin administered after the meal in the diabetic patients did not have any effect on the postprandial triglyceride or chylomicron responses, the concentration of non-esterified fatty acids was significantly higher (p less than 0.0005) when only a basal infusion of insulin was administered., In Conclusion: 1) Short-term deterioration in glycaemic control does not adversely affect lipoprotein concentrations in Type 1 diabetes. 2) Non-esterified fatty acids appear to be a more sensitive index of insulinization post-prandially than triglycerides.
- Published
- 1991
- Full Text
- View/download PDF
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