Tissue Lipid Uptake Research Articles

In Vivo Tissue Lipid Uptake in Antisense Oligonucleotide (ASO)-Treated Mice.

The prevalence of obesity has increased to pandemic levels over the past years. Associated comorbidities linked with the accumulation of lipids in different tissues and blood are responsible for the high mortality in these patients. The increased dietary lipid uptake contributes to these metabolic diseases. Identifying which pathways might be dysregulated in these patients will contribute to find new therapeutic targets. Thus, here, a protocol to follow up the distribution of dietary lipids in blood and tissues is provided. For this, radiolabeled triglyceride in olive oil is administered by oral gavage. To ascertain more precisely the capacity of each tissue for fatty acid uptake, not considering the intestinal barrier, the intravenous (IV) administration of radiolabeled lipids is also described.

Endothelial Cell Receptors in Tissue Lipid Uptake and Metabolism.

Lipid uptake and metabolism are central to the function of organs such as heart, skeletal muscle, and adipose tissue. Although most heart energy derives from fatty acids (FAs), excess lipid accumulation can cause cardiomyopathy. Similarly, high delivery of cholesterol can initiate coronary artery atherosclerosis. Hearts and arteries-unlike liver and adrenals-have nonfenestrated capillaries and lipid accumulation in both health and disease requires lipid movement from the circulation across the endothelial barrier. This review summarizes recent in vitro and in vivo findings on the importance of endothelial cell receptors and uptake pathways in regulating FAs and cholesterol uptake in normal physiology and cardiovascular disease. We highlight clinical and experimental data on the roles of ECs in lipid supply to tissues, heart, and arterial wall in particular, and how this affects organ metabolism and function. Models of FA uptake into ECs suggest that receptor-mediated uptake predominates at low FA concentrations, such as during fasting, whereas FA uptake during lipolysis of chylomicrons may involve paracellular movement. Similarly, in the setting of an intact arterial endothelial layer, recent and historic data support a role for receptor-mediated processes in the movement of lipoproteins into the subarterial space. We conclude with thoughts on the need to better understand endothelial lipid transfer for fuller comprehension of the pathophysiology of hyperlipidemia, and lipotoxic diseases such as some forms of cardiomyopathy and atherosclerosis.

Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation.

iNOS, an important mediator of inflammation, has emerged as an important metabolic regulator. There are conflicting observations on the incidence of insulin resistance (IR) due to hyperglycemia/dyslipidemia in iNOS−/− mice. There are reports that high fat diet (HFD) fed mice exhibited no change, protection, or enhanced susceptibility to IR. Similar observations were also reported for low fat diet (LFD) fed KO mice. In the present study chow fed iNOS−/− mice were examined for the incidence of IR, and metabolic perturbations, and also for the effect of sodium nitrite supplementation (50 mg/L). In IR-iNOS−/− mice, we observed significantly higher body weight, BMI, adiposity, blood glucose, HOMA-IR, serum/tissue lipids, glucose intolerance, enhanced gluconeogenesis, and disrupted insulin signaling. Expression of genes involved in hepatic and adipose tissue lipid uptake, synthesis, oxidation, and gluconeogenesis was upregulated with concomitant downregulation of genes for hepatic lipid excretion. Nitrite supplementation restored NO levels, significantly improved systemic IR, glucose tolerance, and also reduced lipid accumulation by rescuing hepatic insulin sensitivity, glucose, and lipid homeostasis. Obesity, gluconeogenesis, and adipose tissue insulin signaling were only partially reversed in nitrite supplemented iNOS−/− mice. Our results thus demonstrate that nitrite supplementation to iNOS−/− mice improves insulin sensitivity and metabolic homeostasis, thus further highlighting the metabolic role of iNOS.

GIP-induced vasodilation in human adipose tissue involves capillary recruitment.

Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increase blood flow and triglyceride clearance in subcutaneous abdominal adipose tissue in lean humans. The present experiments were performed to determine whether the increase involves capillary recruitment. Eight lean healthy volunteers were studied before and after 1 h infusion of GIP or saline during a hyperglycemic–hyperinsulinemic clamp, raising plasma glucose and insulin to postprandial levels. Subcutaneous abdominal adipose tissue blood flow (ATBF) was measured by the 133Xenon clearance technique, and microvascular blood volume was determined by contrast-enhanced ultrasound imaging. During infusion of saline and the clamp, both ATBF (2.7 ± 0.5 mL/min 100 g/tissue) and microvascular blood volume remained unchanged throughout the experiments. During GIP infusion and the clamp, ATBF increased ~fourfold to 11.4 ± 1.9 mL/min 100 g/tissue, P < 0.001. Likewise, the contrast-enhanced ultrasound signal intensity, a measure of the microvascular blood volume, increased significantly 1 h after infusion of GIP and the clamp (P = 0.003), but not in the control experiments. In conclusion, the increase in ATBF during GIP infusion involves recruitment of capillaries in healthy lean subjects, which probably increases the interaction of circulating lipoproteins with lipoprotein lipase, thus promoting adipose tissue lipid uptake.

Human adipose tissue microvascular endothelial cells secrete PPARγ ligands and regulate adipose tissue lipid uptake.

Human adipose cells cannot secrete endogenous PPARγ ligands and are dependent on unknown exogenous sources. We postulated that the adipose tissue microvascular endothelial cells (aMVECs) cross-talk with the adipose cells for fatty acid (FA) transport and storage and also may secrete PPARγ ligands. We isolated aMVECs from human subcutaneous adipose tissue and showed that in these cells, but not in (pre)adipocytes from the same donors, exogenous FAs increased cellular PPARγ activation and markedly increased FA transport and the transporters FABP4 and CD36. Importantly, aMVECs only accumulated small lipid droplets and could not be differentiated to adipose cells and are not adipose precursor cells. FA exchange between aMVECs and adipose cells was bidirectional, and FA-induced PPARγ activation in aMVECs was dependent on functional adipose triglyceride lipase (ATGL) protein while deleting hormone-sensitive lipase in aMVECs had no effect. aMVECs also released lipids to the medium, which activated PPARγ in reporter cells as well as in adipose cells in coculture experiments, and this positive cross-talk was also dependent on functional ATGL in aMVECs. In sum, aMVECs are highly specialized endothelial cells, cannot be differentiated to adipose cells, are adapted to regulating lipid transport and secreting lipids that activate PPARγ, and thus, regulate adipose cell function.

Hepatic triacylglycerol secretion, lipid transport and tissue lipid uptake in blunt snout bream (Megalobrama amblycephala) fed high-fat diet

High-fat diets may have favorable effects on growth partly based on protein-sparing, but high-fat diets often lead to excessive fat deposition in the liver of some fish. The goal of the study was therefore to investigate effects of fat-rich diet on mechanisms involved in fat deposition in the liver. Three hundred blunt snout bream (Megalobrama amblycephala) juveniles (initial weight 18.00±0.05g) were fed with two diets (5% or 15% fat) for 8weeks. Histological and biochemical parameters were determined. The hepatic triacylglycerol (TG) secretion rate was measured by intraperitoneal injection with poloxamer 407 (a lipoprotein lipase inhibitor). Lipid transport was studied by determining components of lipoproteins. We also examined lipid uptake by assaying lipoprotein lipase (LPL) activities and mRNA expressions in tissues. Our results showed that ultrastructural lesions of organelles in hepatocytes occurred after intake of a high-fat diet. The hepatic TG secretion rate and plasma very low density lipoprotein (VLDL) amount of fish fed high-fat diet were significantly lower compared to those of fish fed control diet. Concomitantly, variations of components of lipoproteins were also apparent. In the liver, muscle and mesenteric fat tissue, the percentage of polyunsaturated fatty acid (PUFA) was significantly increased, while both saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) percentages decreased in high-fat group. Both activities and mRNA expressions of LPL were also increased in these tissues. On the whole, a low level of lipid transport out of the liver, alterations of lipid transport and elevated lipid uptake contributed to fatty liver of blunt snout bream fed high-fat diet.

Thermoneutrality modifies the impact of hypoxia on lipid metabolism

Hypoxia has been shown to rapidly increase triglycerides in mice by decreasing plasma lipoprotein clearance. However, the usual temperature of hypoxic exposure is below thermoneutrality for mice, which may increase thermogenesis and energy requirements, resulting in higher tissue lipid uptake. We hypothesize that decreased lipid clearance and ensuing hyperlipidemia are caused by hypoxic suppression of metabolism at cold temperatures and, therefore, would not occur at thermoneutrality. Twelve-week-old, male C57BL6/J mice were exposed to 6 h of 10% O₂ at the usual temperature (22°C) or thermoneutrality (30°C). Acclimation to 22°C increased lipid uptake in the heart, lungs, and brown adipose tissue, resulting in lower plasma triglyceride and cholesterol levels. At this temperature, hypoxia attenuated lipid uptake in most tissues, thereby raising plasma triglycerides and LDL cholesterol. Thermoneutrality decreased tissue lipid uptake, and hypoxia did not cause a further reduction in lipid uptake in any organs. Consequently, hypoxia at thermoneutrality did not affect plasma triglyceride levels. Unexpectedly, plasma HDL cholesterol increased. The effect of hypoxia on white adipose tissue lipolysis was also modified by temperature. Independent of temperature, hypoxia increased heart rate and glucose and decreased activity, body temperature, and glucose sensitivity. Our study underscores the importance of ambient temperature for hypoxia research, especially in studies of lipid metabolism.

Major involvement of mTOR in the PPARγ-induced stimulation of adipose tissue lipid uptake and fat accretion

Evidence points to a role of the mammalian target of rapamycin (mTOR) signaling pathway as a regulator of adiposity, yet its involvement as a mediator of the positive actions of peroxisome proliferator-activated receptor (PPAR)γ agonism on lipemia, fat accretion, lipid uptake, and its major determinant lipoprotein lipase (LPL) remains to be elucidated. Herein we evaluated the plasma lipid profile, triacylglycerol (TAG) secretion rates, and adipose tissue LPL-dependent lipid uptake, LPL expression/activity, and expression profile of other lipid metabolism genes in rats treated with the PPARγ agonist rosiglitazone (15 mg/kg/day) in combination or not with the mTOR inhibitor rapamycin (2 mg/kg/day) for 15 days. Rosiglitazone stimulated adipose tissue mTOR complex 1 and AMPK and induced TAG-derived lipid uptake (136%), LPL mRNA/activity (2- to 6-fold), and fat accretion in subcutaneous (but not visceral) white adipose tissue (WAT; 50%) and in brown adipose tissue (BAT; 266%). Chronic mTOR inhibition attenuated the upregulation of lipid uptake, LPL expression/activity, and fat accretion induced by PPARγ activation in both subcutaneous WAT and BAT, which resulted in hyperlipidemia. In contrast, rapamycin did not affect most of the other WAT lipogenic genes upregulated by rosiglitazone. Together these findings demonstrate that mTOR is a major regulator of adipose tissue LPL-mediated lipid uptake and a critical mediator of the hypolipidemic and lipogenic actions of PPARγ activation.

Replacing dietary fish oil by vegetable oils has little effect on lipogenesis, lipid transport and tissue lipid uptake in rainbow trout (Oncorhynchus mykiss)

In order to investigate the effects of dietary lipid sources on mechanisms involved in lipid deposition, two groups of rainbow trout were fed from first-feeding to the commercial size of 1 kg (for 62 weeks) with two diets differing only by lipid source: 100% fish oil or 100% blend of vegetable oils (55% rapeseed oil, 30% palm oil, 15% linseed oil). The activities and levels of gene expression of lipogenic enzymes (fatty acid synthetase, glucose-6-phosphate dehydrogenase and malic enzyme) in liver and of lipoprotein lipase in perivisceral adipose tissue, white muscle and liver were determined. Transport of lipid was studied by determining lipid composition of plasma and lipoprotein classes. We also examined the clearance of LDL by assaying the level of LDL receptor gene expression in several tissues. Total replacement of dietary fish oil by the blend of vegetable oils did not affect growth of rainbow trout and did not modify muscle lipid content. Hepatic lipogenesis and lipid uptake in perivisceral adipose tissue, white muscle and liver were also not modified by dietary treatments. Diets containing the blend of vegetable oils induced a decrease in plasma cholesterol and LDL. In trout fed the vegetable oils diet, expression of LDL receptor gene in the liver was down-regulated.

Replacement of a large portion of fish oil by vegetable oils does not affect lipogenesis, lipid transport and tissue lipid uptake in European seabass ( Dicentrarchus labrax L.)

In order to investigate the impact of dietary lipid sources on mechanisms involved in lipid deposition, three groups of European seabass fingerlings with average initial body weight of 5.2 ± 1.0 g were fed three diets differing only by lipid source. These diets were: 100% anchovy oil (diet A), 40% anchovy oil–60% mix of vegetable oils (35% linseed, 15% palm, 10% rapeseed) (diet B) and 40% anchovy oil–60% mix of vegetable oils (24% linseed, 12% palm, 24% rapeseed) (diet C). After 64 weeks of rearing, when seabass reached the size of 160 g, the activity of lipogenic enzymes (fatty acid synthetase, glucose-6-phosphate dehydrogenase and malic enzyme) in liver and of lipoprotein lipase (LPL) in perivisceral adipose tissue, liver and white muscle were measured. Transport of lipid by lipoproteins was examined by determining plasma lipid composition and lipoprotein classes. Dietary oil source did not modify growth performance or lipid content of flesh and liver of seabass. Replacement of 60% of fish oil by the two mixtures of vegetable oils had no significant effect on hepatic lipogenesis and activity of LPL in liver and adipose tissue. Activity of LPL in white muscle was decreased in fish fed diet C compared to those fed diets A and B. Diets containing the mixture of vegetable oils led to lowered plasma, VLDL and LDL cholesterol levels compared to diet A. It is concluded that replacing 60% of fish oil by the two mixtures of vegetable oils in the feeds of European seabass fingerlings until they reach the size of 160 g has no marked effect on growth performance, lipogenesis and tissue lipid uptake but has a hypocholesterolemic effect.

The morphology and metabolism of intraabdominal adipose tissue in men

Mass, morphology, and metabolism of total adipose tissue and its subcutaneous, visceral, and retroperitoneal subcompartments were examined in 16 men with a wide variation of total body fat. Computerized tomography (CT) scans showed that the intraabdominal fat mass comprised approximately 20% of total fat mass. Visceral and retroperitoneal fat masses were approximately 80% and 20% of total intraabdominal fat mass, respectively. Enlargement of intraabdominal fat depots was due to a parallel adipocyte enlargement only. Direct significant correlations were found between these adipose tissue masses and blood glucose and plasma insulin levels, blood pressure, and liver function tests, while glucose disposal rate during euglycemic glucose clamp measurements at submaximal insulin concentrations (GDR), plasma testosterone, and sex hormone-binding globulin concentrations correlated negatively. The correlations for glucose, insulin, and GDR were strongest with visceral fat mass. Adipose tissue lipid uptake, measured after oral administration of labeled oleic acid in triglyceride, was approximately 50% higher in omental than in subcutaneous adipose tissues. Adipocytes from omental fat also showed a higher lipolytic sensitivity and responsiveness to catecholamines. Furthermore, these adipocytes were less sensitive to the antilipolytic effects of insulin. Both lipid uptake and lipolytic sensitivity and responsiveness showed strong correlations ( r = 0.8 to 0.9) to blood glucose and plasma insulin concentrations and also to the GDR (negative), while no such correlations were found with lipid uptake in subcutaneous or retroperitoneal abdominal adipose tissues. Taken together, these results suggest a higher turnover of lipids in visceral than in the other fat depots, which is closely correlated to systemic insulin resistance and glucose metabolism in men.

Uptake of triglyceride fatty acids in adipose tissue in vivo in man

Currently available information on adipose tissue metabolism in man is mainly based on studies in vitro. In the present work adipose tissue lipid uptake was studied in vivo in man. 100 g glucose and 120 g milk fat with 10 microCi U-14C oleic acid were given in the overnight fasting state to eight women and 2 h after a carbohydrate-rich meal to eight women. After 4 h, 1-day, 1 week and 1 month radioactivity levels were determined in the lipids of adipose tissue in the femoral and abdominal regions and in plasma. At 4 h 30 and 20% of the oleic acid was estimated to remain in the extracellular space in the fasted and fed groups respectively, measured in plasma. Contents of oleic acid radioactivity was higher in the abdominal than femoral region. An estimated 27 and 46 g of fat was taken up in adipose tissue of the fasted and fed groups, constituting 1/3 and 1/2 of total tissue uptake respectively. After 1 day these figures were 43 and 60 g respectively. At 1 week and 1 month adipose tissue radioactivity was increasing slowly. Lipoprotein lipase (LPL) activity in adipose tissue at 4 h was higher in the femoral than abdominal adipose tissue and higher in the fed than fasted state in the abdominal region. A significant correlation was found between uptake and LPL in abdominal adipose tissue only. These results show that uptake of fat measured in vivo is probably not necessarily reflected by LPL measurements only, suggesting other regulatory factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein Lipase Activity in Adipose Tissue and in Postheparin Plasma in Human Obesity

ABSTRACT The mechanism by which obesity influences the metabolism of circulating triglycerides was assessed by determination of lipoprotein lipase (LPL) activity in adipose tissue and in postheparin plasma of 26 normolipidemic obese and 26 normal‐weight subjects. Furthermore, the uptakes of VLDL triglyceride and FFA by adipose tissue in vitro were measured in these two groups. The heparin‐releasable LPL activity per weight unit of adipose tissue was similar in obese and normal‐weight subjects but the LPL activity per fat cell was on an average twice as high in obese as in non‐obese subjects. Also the VLDL triglyceride and FFA uptakes by adipose tissue were similar in obese and non‐obese groups when related to tissue weight but both were increased in obese fat cells compared with those of non‐obese. When expressed per total body fat, all these parameters of adipose tissue lipid uptake were higher in obese than in normal‐weight subjects. In contrast, the obese group did not show any increase in the postheparin plasma LPL activity but rather a tendency for the values to accumulate in the low normal range. Serum triglyceride concentration was not related to any of the LPL activities or to tissue lipid uptake in separate or combined obese and non‐obese groups. Serum basal insulin level and insulin response to glucose were significantly higher in the obese than in non‐obese subjects but in spite of this, the serum triglyceride level was similar in the two groups. Stepwise multiple regression analysis showed that all the measured parameters of adipose tissue were positively correlated to fat cell size but when the latter was held constant, the fat cell VLDL triglyceride uptake was still related to cell LPL activity and to serum insulin concentration. These results suggest that in obesity the adipose tissue has an increased capacity to remove circulating triglycerides.

The Influence of Feeding Ascorbic Acid and Sulfate on Egg Production and on Cholesterol Content of Certain Tissues of the Hen ,

Continuously feeding 1333 p.p.m. ascorbic acid to S.C.W.L. chicks resulted in delayed onset of egg production compared to controls. Ascorbate fed hens had increased (P < 0.05) percent liver lipids and decreased (P < 0.05) percent thigh muscle (semitendinosus) lipids compared to controls. Supplementing ascorbate fed hens with 1.0% sulfate decreased (P < 0.05) percent liver lipids relative to hens fed ascorbate. Sulfate ingestion by either ascorbate hens or controls reduced thigh cholesterol concentrations. While liver cholesterol levels were highest in ascorbate fed birds, their adipose tissue contained the least concentration. Control hens fed sulfate had the lowest liver cholesterol content and the highest adipose concentration of the different treatments. There is possibly a problem in liver lipid mobilization or tissue lipid uptake when ascorbic acid is ingested. Sulfate feeding to control and ascorbate hens resulted in reduced muscle cholesterol compared to controls. Eggs were collected from individual ascorbate fed hens before and after 1.0% sulfate was included in their diet. Sulfate ingestion increased the total egg cholesterol significantly (P < 0.05). Ascorbic acid may have sulfated the cholesterol, which enhanced its mobilization from tissues such as muscle and promoted its excretion into the egg. Plasma cholesterol levels were not influenced by treatments.