triolein and Hypertriglyceridemia

Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12-weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared with wildtype mice, with a reduction of white and brown adipose tissues. Partitioning of dietary [

Topics: Adipose Tissue, Brown; Animals; Cachexia; Hypertriglyceridemia; Mice; Mitophagy; Mucopolysaccharidosis III; Triolein

Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH) during sleep and is associated with elevated triglycerides (TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO(2) = 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dose-dependently increased plasma TG, with levels peaking at FiO(2) = 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO(2) = 0.10. Plasma catecholamines also increased inversely with FiO(2). Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO(2) = 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing [(3)H]triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-γ, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion.

Topics: Acute Disease; Animals; Dietary Fats; Emulsions; Fat Emulsions, Intravenous; Hypertriglyceridemia; Hypoxia; Lipolysis; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Oxygen; Phospholipids; Soybean Oil; Triglycerides; Triolein; Up-Regulation

Postprandial hypertriglyceridemia (PHTG) has been shown repeatedly to be associated with metabolic syndrome and atherosclerotic cardiovascular diseases. We have recently reported that ezetimibe inhibits PHTG in patients with type IIb hyperlipidemia. Ezetimibe was also reported to atten-uate PHTG in combination with low-dose statins in patients with obesity or metabolic syndrome. We reported CD36-deficient (CD36KO) mice as a new model for PHTG, in which the synthesis of chylomicron (CM) in the small intestines is enhanced. In the current study, we investigated the effect of ezetimibe on PHTG in this mouse model of metabolic syndrome.. Wild-type (WT) mice fed a western diet, and CD36KO mice fed a normal chow diet, respectively, were treated for 3 weeks with and without ezetimibe, followed by an evaluation of triglyceride (TG) concentrations by enzymatic method and by high performance liquid chromatogra-phy (HPLC) as well as those of and apolipoprotein (Apo) B-48 in plasma and intestinal lymph after oral fat loading with olive oil. Intestinal mucosa was also harvested to evaluate the transcriptional regulation of the genes involved in the intestinal production of ApoB-containing lipoproteins.. Ezetimibe dramatically reduced PHTG in both WT and CD36KO mice. HPLC analysis of plasma showed that the decrease in TG content in CM and CM remnants-sized particles contributed to this suppression, suggesting that CM production in the small intestines might be reduced after ezetimibe treatment. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. Both TG content and ApoB-48 mass were decreased in ezetimibe-treated mice. The quantitative RT-PCR of intestinal mucosa showed down-regulation of the mRNA expression of FATP4 and ApoB in both groups along with FABP2, DGAT1, DGAT2 and SCD1 in WT mice at postprandial state after ezetimibe treatment.. Ezetimibe alone reduces PHTG by blocking both the absorption of cholesterol and the intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, resulting in the reduction of the formation of ApoB-48 which is necessary for the ApoB48-containing lipoprotein production in the small intestines.

Topics: Animals; Anticholesteremic Agents; Apolipoprotein B-48; Azetidines; Base Sequence; CD36 Antigens; Chylomicrons; Disease Models, Animal; DNA Primers; Ezetimibe; Fatty Acid Transport Proteins; Fatty Acid-Binding Proteins; Hypertriglyceridemia; Intestinal Absorption; Lipoproteins, VLDL; Lymph; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Postprandial Period; RNA, Messenger; Triglycerides; Triolein

In humans and animal models, high plasma concentrations of apolipoprotein (apo) E are associated with hypertriglyceridemia. It has been shown that overexpression of human wild-type (WT) apoE4 in apoE-deficient mice induces hypertriglyceridemia. In contrast, overexpression of an apoE4 variant, apoE4-mut1 (apoE4(L261A, W264A, F265A, L268A, V269A)), does not induce hypertriglyceridemia and corrects hypercholesterolemia. Furthermore, overexpression of another variant, apoE4-mut2 (apoE4(W276A, L279A, V280A, V283A)), induces mild hypertriglyceridemia and does not correct hypercholesterolemia. To better understand how these mutations improve the function of apoE4, we investigated the conformation and stability of apoE4-mut1 and apoE4-mut2 and their binding to dimyristoyl phosphatidylcholine (DMPC) vesicles and to triglyceride (TG)-rich emulsion particles. We found that the mutations introduced in apoE4-mut1 lead to a more stable and compactly folded conformation of apoE4. These structural changes are associated with a slower rate of solubilization of DMPC vesicles by apoE4-mut1 and reduced binding of the protein to emulsion particles compared with WT apoE4. Under conditions of apoE4 overexpression, the reduced binding of apoE4-mut1 to TG-rich lipoprotein particles may facilitate the lipolysis of these particles and may alter the conformation of the lipoprotein-bound apoE in a way that favors the efficient clearance of the lipoprotein remnants. Mutations introduced in apoE4-mut2 result in smaller structural alterations compared with those observed in apoE4-mut1. The slightly altered structural properties of apoE4-mut2 are associated with slightly reduced binding of this protein to TG-rich lipoprotein particles and milder hypertriglyceridemia as compared with WT apoE4.

Topics: Amino Acid Sequence; Anilino Naphthalenesulfonates; Apolipoprotein E4; Cell Line; Circular Dichroism; Dimyristoylphosphatidylcholine; Humans; Hypertriglyceridemia; Lipoproteins, VLDL; Microscopy, Electron; Molecular Sequence Data; Mutant Proteins; Mutation; Protein Denaturation; Protein Folding; Protein Stability; Protein Structure, Secondary; Solubility; Temperature; Triolein

Obesity is associated with cognitive impairments. Long-term mechanisms for this association include consequences of hyperglycemia, dyslipidemia, or other factors comprising metabolic syndrome X. We found that hypertriglyceridemia, the main dyslipidemia of metabolic syndrome X, is in part responsible for the leptin resistance seen in obesity. Here we determined whether triglycerides have an immediate and direct effect on cognition. Obese mice showed impaired acquisition in three different cognitive paradigms: the active avoidance T-maze, the Morris water maze, and a food reward lever press. These impairments were not attributable to differences in foot shock sensitivity, swim speed, swimming distance, or voluntary milk consumption. Impaired cognition in obese mice was improved by selectively lowering triglycerides with gemfibrozil. Injection into the brain of the triglyceride triolein, but not of the free fatty acid palmitate, impaired acquisition in normal body weight mice. Triolein or milk (97% of fats are triglycerides), but not skim milk (no triglycerides), impaired maintenance of the N-methyl-d-aspartate component of the hippocampal long-term synaptic potential. Measures of oxidative stress in whole brain were reduced by gemfibrozil. We conclude that triglycerides mediate cognitive impairment as seen in obesity, possibly by impairing maintenance of the N-methyl-d-aspartate component of hippocampal long-term potentiation, and that lowering triglycerides can reverse the cognitive impairment and improve oxidative stress in the brain.

Topics: Animals; Avoidance Learning; Cognition Disorders; Diet, Atherogenic; Excitatory Postsynaptic Potentials; Gemfibrozil; Hypertriglyceridemia; Hypolipidemic Agents; Lipid Peroxidation; Male; Maze Learning; Memory; Mice; Mice, Inbred Strains; Obesity; Swimming; Triolein

The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia.. Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35 mg/kg per day) for 2 weeks resulted in a 2-fold increase in fasting plasma triglyceride (TG) levels, which was specific for very low-density lipoprotein (VLDL). RTV did not change the hepatic VLDL-TG production. Instead, RTV did increase the postprandial TG response to an oral fat load (area under the curve, 25.5+/-12.1 versus 13.8+/-6.8 mmol/L per hour in controls; P<0.05). Likewise, RTV hampered the plasma clearance of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (half time, 19.3+/-10.5 versus 5.0+/-1.3 minutes in controls; P<0.05) associated with a decrease of 44% in plasma lipoprotein lipase activity. Accordingly, RTV decreased the uptake of TG-derived fatty acids (FAs) into adipose tissue, as well as the uptake of albumin-bound FA.. We conclude that RTV causes hypertriglyceridemia via decreased lipoprotein lipase-mediated clearance of VLDL-TG. In addition, RTV specifically impairs the uptake of FA in adipose tissue, which may contribute to the lipodystrophy that is frequently observed in HIV-infected subjects on antiretroviral therapy.

Topics: Adipose Tissue; Animals; Anticoagulants; Apolipoprotein E3; Apolipoproteins E; Cholesterol, VLDL; Emulsions; Enzyme Activation; Fatty Acids; Female; Heparin; HIV Infections; HIV Protease Inhibitors; Hypertriglyceridemia; Lipolysis; Lipoprotein Lipase; Mice; Mice, Transgenic; Postprandial Period; Ritonavir; Triglycerides; Triolein; Tritium

Because obesity, insulin resistance, and hyperlipidemia are often associated, and recent evidence suggests that the cytokine tumor necrosis factor-alpha (TNF) may influence the activity of insulin in various target tissues, the present study was designed to see whether TNF was also associated with the changes in lipid metabolism that lead to hyperlipidemia in the obese model of the Zucker rat. A polyclonal goat anti-rat TNF antibody was subcutaneously administered to Zucker rats for 4 days to block TNF actions. The results indicate that none of the alterations in lipid metabolism seen in the obese animals were reversed by the anti-TNF treatment. This was the case for the lipogenic rate in liver and adipose tissue, the disposal of an exogenous [14C]triolein load, adipose tissue lipoprotein lipase activity, and the hypertriglyceridemia. Measurements of lipolysis in adipose tissue slices from the anti-TNF-treated animals also did not show any significant effect of the treatment. In conclusion, TNF does not seem to be involved in the abnormalities of lipid metabolism observed in the obese Zucker rat.

Topics: Adipose Tissue; Animals; Antibodies; Hypertriglyceridemia; Lipid Metabolism; Lipoprotein Lipase; Liver; Male; Obesity; Rats; Rats, Zucker; Triolein; Tumor Necrosis Factor-alpha

Heparin-Sepharose chromatography was used to separate Sf 60-400 very-low-density lipoproteins (VLDL) from type IV hypertriglyceridemic subjects into apolipoprotein (apo) E-poor and apo E-rich subfractions. Since we have previously demonstrated that the apo E-poor fraction accumulates in plasma of type IV subjects, the aim of the present studies was to determine whether it was resistant to lipolysis in comparison to the apo E-rich fraction. The apo E-rich fraction was found to be 30% more effective than the apo E-poor fraction at competing with a glycerol tri[1-14C]oleate emulsion for in vitro lipolysis by normolipidemic human post-heparin plasma (P < .01), when assayed under conditions in which both lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) were active. Similar results were obtained when bovine milk LPL was used as the source of lipolytic activity (P < .025 for apo E-rich relative to apo E-poor VLDL), while neither fraction competed effectively with the synthetic substrate for lipolysis by HTGL only. When equal amounts of triglyceride from VLDL subfractions were incubated with bovine milk LPL, 25% more free fatty acid was released from the apo E-rich fraction than from the apo E-poor fraction (P < .025). The effects of heparin-induced lipolysis in vivo in type IV subjects on the relative amounts and composition of these VLDL subfractions were also assessed. Heparin infusion was associated with a 50% reduction in plasma Sf 60-400 VLDL triglyceride concentration. In addition, heparin-induced lipolysis resulted in a marked decrease in the relative amount of apo E-rich VLDL, while the relative amount of apo E-poor VLDL was increased. These results demonstrate that the apo E-poor VLDL subfraction is resistant to lipolysis by LPL relative to its apo E-rich counterpart, suggesting that reduced lipolytic efficiency may contribute to its observed accumulation in plasma of type IV subjects.

Topics: Animals; Apolipoproteins E; Cattle; Chemical Fractionation; Heparin; Humans; Hypertriglyceridemia; Lipase; Lipolysis; Lipoprotein Lipase; Lipoproteins, VLDL; Liver; Milk; Reference Values; Triolein

Tumour necrosis factor alpha (cachectin) was administered to virgin, lactating and litter-removed rats, and subsequent disposal of an oral [1-14C]triolein (glycerol tri[1-14C]oleate) load examined. Absorption of the lipid and 14CO2 production were significantly depressed in all three groups. [14C]Lipid accumulation was decreased in carcass, liver and adipose tissue (brown and white) of virgin and litter-removed rats and the mammary gland of lactating rats. The plasma triacylglycerol concentration was increased in all three groups, and lipoprotein lipase activity was decreased in the white adipose tissue of virgin and litter-removed animals and in the mammary gland of lactating animals. Some, but not all, of these effects mimic tumour burden in the same physiological states [Evans & Williamson (1988) Biochem. J. 252, 65-72].

Topics: Adipose Tissue; Animals; Female; Hypertriglyceridemia; Lactation; Lipoprotein Lipase; Mammary Glands, Animal; Neoplasms; Pregnancy; Rats; Rats, Inbred Strains; Triolein; Tumor Necrosis Factor-alpha