Responses of adipose tissue lipoprotein lipase to weight loss affect lipid levels and weight regain in women

This study determines whether changes in abdominal (ABD) and gluteal (GLT) adipose tissue lipoprotein lipase (LPL) activity in response to a 6-mo weight loss intervention, comprised of a hypocaloric diet and low-intensity walking, affect changes in body composition, fat distribution, lipid metabolism, and the magnitude of weight regain in 36 obese postmenopausal women. Average adipose tissue LPL activity did not change with an average 5.6-kg weight loss, but changes in LPL activity were inversely related to baseline LPL activity (ABD: r = -0.60, GLT: r = -0.48; P < 0.01). The loss of abdominal body fat and decreases in total and low-density lipoprotein cholesterol were greater in women whose adipose tissue LPL activity decreased with weight loss despite a similar loss of total body weight and fat mass. Moreover, weight regain after a 6-mo follow-up was less in women whose adipose tissue LPL activity decreased than in women whose LPL increased (ABD: 0.9 +/- 0.5 vs. 2.8 +/- 0.6 kg, P < 0.05; GLT: 0.2 +/- 0.5 vs. 2.8 +/- 0.5 kg, P < 0.01). These results suggest that a reduction in adipose tissue LPL activity with weight loss is associated with improvements in lipid metabolic risk factors with weight loss and with diminished weight regain in postmenopausal women.     

Lipoprotein lipase activity is stimulated by insulin and dexamethasone in cardiomyocytes from diabetic rats.

Type 1 diabetes mellitus reduces lipoprotein lipase (LPL) activity in the heart. The diabetic phenotype of decreased LPL activity in freshly isolated cardiomyocytes persisted after overnight culture (16 h). Total cellular LPL activity was 311+/-56 nmol oleate released x h(-1) x mg(-1) cell protein in diabetic cultured cardiomyocytes compared with 661+/-81 nmol oleate released x h(-1) x mg(-1) cell protein for control cultured cells. Diabetes also resulted in lower heparin-releasable (HR) LPL activity compared with control cells (111+/-25 vs. 432+/-63 nmol x h(-1) x mg(-1) cell protein). In kinetic experiments, the reduction in total cellular LPL and HR-LPL activities in cultured cells from diabetic hearts was due to a decrease in maximal velocity, with no change in apparent Km for substrate (triolein). LPL activity in primary cultures of cardiomyocytes from control rats is stimulated by the combination of insulin (Ins) and dexamethasone (Dex). Overnight treatment of cultured cardiomyocytes from diabetic rats with Ins+Dex elicited an 84% increase in cellular LPL activity (to 572+/-65 nmol x h(-1) x mg(-1) cell protein) and a 194% increase in HR-LPL activity (to 326+/-46 nmol x h(-1) x mg(-1) cell protein). This stimulation occurred at subnanomolar concentrations of the hormones, but neither hormone was effective alone. The amount of immunoreactive LPL protein mass in cultured cardiomyocytes from diabetic hearts was unchanged by Ins+Dex treatment. Addition of oleic acid (60 microM) to the overnight culture medium inhibited the already reduced HR-LPL activity in diabetic cultured cells by 73% (to 30+/-4 nmol x h(-1) x mg(-1) cell protein). The presence of oleic acid also reduced hormone-stimulated HR-LPL activity. Increasing the glucose concentration in the culture medium to 26 mM had no effect on total cellular LPL or HR-LPL activities.     

Adipose, muscle and lung tissue lipoprotein lipase activities in young streptozotocin treated rats

Lipoprotein lipase (LPL) activity was studied in adipose, muscle and lung tissues of post-weanling rats 48 and 96 hours after experimentally induced diabetes by streptozotocin administration. Weight gain was reduced, and blood glucose level increased about 3-4 fold above the control level as an indication of the diabetic state. LPL activity in brown and white adipose tissues decreased in diabetic rats to 10-30% of the control level. In soleus muscle the LPL activity was slightly enhanced 96 hours after the streptozotocin injection. In cardiac muscle the LPL activity was markedly increased already 48 hours after the administration of streptozotocin and the increase remained significant until 96 hours. There was in the pulmonary tissue also an increase of LPL activity of diabetic rats, although this was significant only 96 hours after streptozotocin treatment. The results suggest marked tissue specific variation in the LPL activity. Moreover, tissue responses to experimentally induced diabetes vary. In adipose tissue the decrease in the LPL activity suggests that lipid transport to adipocytes is decreased while an increase in skeletal and cardiac muscles and in lung tissue proposes that their lipid utilization is enhanced.     

Effects of fasting on lipoprotein lipase activity in different depots of white and brown adipose tissues in diet-induced overweight rats

The aim of the present study was to evaluate the effects of 24 hours of starvation on lipoprotein lipase (LPL) activity in various depots of white and brown adipose tissues in control rats and in rats with two different degrees of overweight, both induced by dietary treatment. In control rats, no changes in LPL immunoreactive mass were observed in either white or brown adipose tissues after fasting, whereas the effects of food deprivation on enzyme activity were opposite in white versus brown adipose tissues. The LPL activity response to fasting was impaired by obesity: White adipose depots of cafeteria obese rats showed a lower ability to downregulate LPL during fasting and the increased LPL activity induced by fasting in brown adipose depots was less intense in the obese rats compared with control animals. When the degree of overweight was reduced, the differences between obese and control rats were also attenuated.     

Regulation of lipoprotein lipase in muscle and adipose tissue during exercise.

Lipoprotein lipase (LPL) is regulated in a tissue-specific manner; exercise increases LPL activity in muscle at the same time it is reduced in adipose tissue. The purpose of this study was to determine the relationship between LPL activity and LPL mRNA in muscle and adipose tissue in rats exposed to one bout of exercise. Immediately after a 2-h swim, LPL activity [pmol free fatty acids (FFA).min-1.mg tissue-1] in the exercised animals was reduced 43% in adipose tissue (110 +/- 26 to 63 +/- 17) and increased almost twofold in the soleus muscle (203 +/- 26 to 383 +/- 59) compared with sedentary control animals. At the same time, LPL mRNA was reduced 42% in adipose tissue and increased 50 and 100% in the red vastus and white vastus muscles, respectively. Twenty-four hours after the swim, LPL activity had returned to control levels in adipose tissue and the soleus muscle. At hour 24 of recovery, LPL mRNA was still reduced 23% in the adipose tissue of exercised animals but was not significantly different between exercised and control animals in any of the muscle tissues analyzed. Changes in total RNA concentration could not account for the changes in relative LPL mRNA expression. The relationship between LPL enzyme activity and LPL mRNA in muscle and adipose tissue was +0.86 and +0.93 at 0 and 24 h postexercise, respectively. Thus the tissue-specific changes in enzyme activity induced by exercise could be mediated, in part, through pretranslational control.     

Insulin regulation of lipoprotein lipase (LPL) activity and expression in gilthead sea bream (Sparus aurata)

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism by virtue of its capacity to hydrolyze triglycerides circulating in the form of lipoprotein particles. Here we analyzed the fasting effects of LPL in gilthead sea bream (Sparus aurata) and also present the first study in fish of the role of insulin as a potential modulator of both LPL activity and expression. Fasting for 2 weeks provoked a clear decrease in adipose tissue LPL activity, concomitant with lower levels of plasma insulin, while no effects were observed in red muscle. To elucidate the specific role of insulin, increases of plasma insulin were experimentally induced by arginine and insulin injections. However, arginine predominantly stimulated glucagon over insulin secretion in this fish species while LPL activity did not change significantly in adipose tissue. Instead, insulin administration induced an increase in adipose tissue LPL activity 3 h after the injection, whereas LPL activity in red muscle was not affected. Changes in LPL activity were accompanied by an increase in LPL mRNA levels in the adipose tissue of insulin-injected gilthead sea bream, although changes in LPL expression were delayed in time with respect to variations in LPL activity. Finally, LPL mRNA levels in red muscle were similar between control and insulin-injected gilthead sea bream, suggesting that insulin does not play a direct role in the regulation of LPL in this tissue. The current study shows that LPL activity is regulated by nutritional condition and underscores the importance of insulin as a modulator of LPL activity and expression in the adipose tissue of gilthead sea bream.     

Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA

The plasma cholesteryl ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high density lipoproteins (HDL) to triglyceride-rich lipoproteins and plays a major role in the catabolism of HDL. Lipoprotein lipase (LPL) is the rate-limiting enzyme for hydrolysis of circulating triglyceride and is involved in HDL formation. We show that tissues containing LPL are major sources of CETP mRNA in several mammalian species, including some with low cholesteryl ester transfer activity in plasma. In hamsters, adipose tissue and heart were found to be the richest sources of both CETP and LPL mRNA; in situ hybridization studies showed that the same cell types (i.e. adipocytes or myocytes) contained CETP and LPL mRNA in these tissues. Isolated adipocytes synthesized active CETP. Dietary studies revealed a complex pattern of response of CETP mRNA levels in different tissues, which showed partial similarity to the changes in LPL mRNA abundance. However, high cholesterol diets resulted in increased CETP mRNA abundance in adipose tissue, heart, and skeletal muscle, without equivalent changes in LPL mRNA. Plasma HDL cholesteryl ester levels showed strong inverse correlations with CETP mRNA abundance in adipose tissue. The results suggest a conserved function of CETP in adipose tissue and heart, such as a co-ordinate action with LPL to enhance HDL turnover. Although there is considerable overlap in the tissue- and cell-specific pattern of CETP and LPL gene expression, dietary studies revealed only limited parallelism in response at the mRNA level. The increase in CETP mRNA in peripheral tissues in response to increased dietary cholesterol suggests that local induction of CETP synthesis may help to recycle cholesterol deposited in these tissues during lipolysis of dietary lipoproteins.     

Lipoprotein lipase gene variation is associated with adipose tissue lipoprotein lipase activity, and lipoprotein lipid and glucose concentrations in overweight postmenopausal women

Adipose tissue lipoprotein lipase (LPL) activity is under strong genetic control in both mice and humans. This study determines whether common DNA variation in the LPL gene (PvuII and HindIII polymorphisms) is associated with adipose tissue LPL activity and metabolic risk factors in a homogeneous population of 75 overweight postmenopausal women (body mass index >25 kg/m2; age: 51-69 years old). The allele frequencies for the presence of the cut-sites for LPL HindIII and PvuII were 0.71 and 0.49, respectively. There were no associations between the HindIII polymorphism and any of the measured variables. Age, body mass index, percent body fat, waist-hip ratio, visceral and subcutaneous fat area, and gluteal (GLT) and abdominal (ABD) adipocyte size did not differ by LPL PvuII genotype. However, adipose tissue LPL activity at both GLT and ABD sites was higher in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous (+/-) or homozygous (+/+) for the cut-site (P<0.05). Total and LDL cholesterol were lower in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous or homozygous for the cut-site (P<0.05), whereas triglyceride and HDL levels were similar between LPL PvuII genotypes. Fasting glucose, but not insulin, was lower in women without the LPL PvuII cut-site (-/-). These data suggest that the LPL PvuII polymorphism is a possible marker for a functional mutation that is found in the LPL gene and that alters LPL activity in older overweight women.     

Lipid metabolism in lipoatrophic diabetes

Some aspects of lipid metabolism were studied in 4 patients with a congenital lipoatrophic diabetes (LAD) associated to a type IV hyperlipoproteinemia. The analysis of lipoprotein composition, expressed as mg/dl, demonstrates a significant increase of VLDL mass and a significant reduction of HDL mass. The analysis of lipoprotein composition, expressed as per cent of total mass demonstrates an increase of the triglyceride content in all fractions and a significant reduction of the cholesterol and phospholipid content in HDL2 particles. Apo C-II, C-III0, C-III1 and C-III2 levels in lipoprotein fractions were normal in LAD patients. Lipoprotein lipase activity in omental adipose tissue, collected during laparoscopy in one patient was undetectable. The serum of this patient did not fully activate the lipoprotein lipase eluted from normal adipose tissue. In all patients the adipose tissue lipoprotein lipase activity in post-heparin plasma was blunted or near absent. Thus a reduced peripheral clearance of triglyceride-rich lipoprotein could be an important determinant of lipoprotein abnormalities in lipoatrophic diabetes.     

Effects of high dose progestin on serum lipids and lipid metabolizing enzymes in patients with endometrial cancer

The effect of high dose medroxyprogesterone acetate (MPA) on serum lipids, on adipose tissue lipoprotein lipase (LPL) and serum lecithin cholesterol acyltransferase activities were studied in 15 postmenopausal patients with endometrial cancer. After 2 weeks of MPA treatment total cholesterol decreased by 14% (P less than 0.001) and HDL cholesterol by 33% (P less than 0.01) from the respective pretreatment values; correspondingly the ratio of HDL to total cholesterol decreased (P less than 0.05). The decrease of HDL2 cholesterol was 35% (P less than 0.01) and that of HDL3 cholesterol 15% (P less than 0.01). The levels of serum triglycerides decreased significantly (P less than 0.05) during the treatment period. Serum LCAT activity was significantly lower (P less than 0.05) after treatment than before, but adipose tissue LPL activity was not altered. The mean serum testosterone level decreased significantly (P less than 0.001) from the pretreatment values. Significant positive correlations were present between LPL activity and MPA concentrations and between LPL activity and testosterone concentrations after the drug treatment.     

Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle.

Hormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (-40%) and TG (-63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (-90%) and strongly decreased ketone body concentrations in plasma (-80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an "anti-atherogenic" lipoprotein profile.     

Overexpression of human apolipoprotein A-II in mice induces hypertriglyceridemia due to defective very low density lipoprotein hydrolysis

Two lines of transgenic mice, hAIItg-delta and hAIItg-lambda, expressing human apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, respectively, displayed on standard chow postprandial chylomicronemia, large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) but greatly reduced high density lipoprotein (HDL). Hypertriglyceridemia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and control mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activities decreased at most by 30% in transgenic mice, whereas adipose tissue and muscle LPL activities were unaffected, indicating normal LPL synthesis. However, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent Vmax of the reaction decreasing proportionately to human apoA-II expression. Human apoA-II was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasma from control mice induced a dose-dependent decrease in LPL and hepatic lipase activities. In conclusion, overexpression of human apoA-II in transgenic mice induced the proatherogenic lipoprotein profile of low plasma HDL and postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL.     

Effect of losartan on insulin plasma concentrations and LPL activity in adipose tissue of hypertensive rats.

The aim of this study is to determine the effect of losartan on insulin and angiotensin II (Ang II) concentrations in plasma as well as on lipoprotein lipase activity (LPL) and angiotensin II content in the adipose tissue of hypertensive rats. Fifty male rats were divided in five groups. Group A served as controls. Group B underwent renal artery stenosis. Group C were administered losartan (10 mg/kg/day) per os, while rats in group D were submitted to renal artery stenosis and were treated with losartan as above. Group E was used as sham-operated control. The animals were sacrificed at day 21. Blood samples were collected, and perirenal adipose tissue was isolated. Furthermore, adrenal's were removed and their relative weight (adrenal weight/body weight) was used as an index of sympathetic stimulation. According to our results, renovascular hypertension resulted in lower insulin concentrations and higher Ang II content in plasma. In hypertensive rats, LPL activity was decreased, while the adrenals' relative weight was elevated. On the other hand, losartan administration resulted in normalization of insulin concentrations in plasma and adrenals' relative weight, with consequent up regulation of LPL activity in adipose tissue. In conclusion, renovascular hypertension interferes in lipid metabolism by reducing LPL activity in adipose tissue, while losartan administration reverses this effect by enhancing insulin release and reducing sympathetic nervous system (SNS) stimulation.     

Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype

We sought to test the hypothesis that dietary long-chain n-3 PUFA (LC n-3 PUFA) in fish oil stimulate the gene expression of lipoprotein lipase (LPL) in human adipose tissue (AT). In a randomized, double blind, placebo-controlled, cross-over study, 51 male subjects expressing an atherogenic lipoprotein phenotype (ALP) had their diets supplemented with fish oil for 6 weeks. As we previously reported for this group, supplementation with LC n-3 PUFA produced a decrease in fasting plasma triglyceride (TG) (-35%, P < 0.05), attenuation of the postprandial TG response (area and incremental area under the curve; AUC and IAUC, P < 0.05), and a decrease in small, dense LDL. The present study extended these observations by showing that these changes were accompanied by a marked increase in the concentration of LPL mRNA in adipose tissue (AT-LPL mRNA, +55%, P = 0.003) and post-heparin LPL activity (PH-LPL, +31%, P = 0.036). There was also evidence of an association between LPL gene expression and polymorphism in the apolipoprotein E gene. We conclude that the favorable influence of dietary n-3 PUFA on the ALP may be mediated, in part, through an increase in the plasma activity and gene expression of lipoprotein lipase in human adipose tissue.     

Modifications of plasma lipoproteins after lipase activation in patients with chylomicronemia

Lipoprotein lipase (LPL) and hepatic lipase (HL) are enzymatic activities involved in lipoprotein metabolism. The purpose of this study was to analyze the physicochemical modifications of plasma lipoproteins produced by LPL activation in two patients with apoC-II deficiency syndrome and by HL activation in two patients with LPL deficiency. LPL activation was achieved by the infusion of normal plasma containing apoC-II and HL was released by the injection of heparin. Lipoproteins were analyzed by ultracentrifugation in a zonal rotor under rate flotation conditions before and after lipase activation. The LPL activation resulted in: a reduction of plasma triglycerides; a reduction of fast-floating very low density lipoprotein (VLDL) concentration; an increase of intermediate density lipoprotein (IDL), which maintained unaltered flotation properties; an increase of low density lipoproteins (LDL) accompanied by modifications of their flotation rates and composition; no significant variations of high density lipoprotein (HDL) levels; and an increase of the HDL flotation rate. The HL activation resulted in: a slight reduction of plasma triglycerides; a reduction of the relative triglyceride content of slow-floating VLDL, IDL, LDL2, and HDL3 accompanied by an increase of phospholipid in VLDL and by an increase of cholesteryl ester in IDL; and a reduction of the HDL flotation rate. These experiments in chylomicronemic patients provide in vivo evidence that LPL and HL are responsible for plasma triglyceride hydrolysis of different lipoproteins, and that LPL is particularly involved in determining the levels and physicochemical properties of LDL. Moreover, in these patients, the LPL activation does not directly change the HDL levels, and LPL or HL does not produce a step-wise conversion of HDL3 to HDL2 (or vice versa) but rather modifies the flotation rates of all the HDL molecules present in plasma.     

Sex-specific differences in leg fat uptake are revealed with a high-fat meal

The mechanism(s) by which sex specific differences in regional body fat distribution develop are not known. We assessed the effects of a high-fat (HF) meal on fatty acid oxidation and uptake into regional fat depots using isotopic tracers and adipose biopsies. Thirty men (BMI 23.6 +/- 0.3 kg/m(2)) and 29 women (BMI 22.4 +/- 0.3 kg/m(2)) received a meal containing [(3)H]triolein. Twelve of the men and 13 of the women received an additional 80 g of triolein in the meal (HF) and the remainder received a normal-fat (NF) meal. Adipose tissue lipoprotein lipase (LPL) activity was measured in the fed and fasted state. After 24 h, meal fatty acid uptake into subcutaneous adipose tissue was assessed. The efficiency of meal fat uptake into upper body subcutaneous fat was similar in both sexes, but women had a greater leg fat uptake, especially in response to a HF meal (P < 0.0001). A correlation between fed-state LPL activity and meal fat uptake was found in both upper and lower body fat (P < 0.0001, r = 0.69). These studies show that, in times of net fat storage, women preferentially increase uptake in leg adipose tissue, and this is likely mediated by fed-state LPL activity.     

Lipoprotein lipase: size of the functional unit determined by radiation inactivation

Radiation inactivation was used to determine the functional molecular weight of lipoprotein lipase (LPL) in rat heart and adipose tissues. This technique reveals the size of the smallest unit required to carry out the enzyme function. Supernatant fractions of the tissue homogenates were exposed to high energy electrons at -135 degrees C. LPL activity showed a simple exponential decay in all samples tested. Because changes in nutritional state shift the distribution of LPL between the capillary endothelial and parenchymal cells within heart and adipose tissues, fasted and refed rats were used for the radiation studies. The functional molecular weight was calculated to be 127,000 +/- 15,000 (mean +/- SD) daltons for heart and adipose. Thus, the smallest unit required for enzyme function was the same in both of these tissues and did not vary with nutritional state. The data suggest that, compared with LPL monomer sizes reported in the range 55,000 to 72,000, this active unit constitutes a dimer.     

Activation of trout adipose tissue lipoprotein lipase by trout apoproteins

In rainbow trout (Salmo gairdnerii) lipoprotein profiles change during the annual sexual cycle. Among other factors, lipoprotein lipase (LPL) activity might play a role. This enzyme is activated by trout serum suggesting the existence of a cofactor corresponding to apoprotein CII in this species. In the present study, we determined more accurately some characteristics of the enzyme activity inhibited by 0.3 M NaCl. Trout serum and high density lipoproteins (HDL) activated both rat and trout adipose tissue LPLs. A fraction of apo HDL obtained by gel filtration also activated the enzyme. The mean Mr was 10,000. Isoelectric focusing of the same fraction gave several bands of proteins with apparent pI in the range of 4.2-4.9. These results show that in trout, LPL is activated by a cofactor similar to that in mammals, the apo CII. In addition, a fraction mainly containing apo AI (+ traces of apo C) activated trout LPL and reinforced the activation by apo CII. These findings suggest that trout apo AI may promote the activating effect of apo CII on trout LPL.     

The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis

The VLDL receptor (VLDLr) is involved in tissue delivery of VLDL-triglyceride (TG)-derived FFA by facilitating the expression of lipoprotein lipase (LPL). However, vldlr-/- mice do not show altered plasma lipoprotein levels, despite reduced LPL expression. Because LPL activity is crucial in postprandial lipid metabolism, we investigated whether the VLDLr plays a role in chylomicron clearance. Fed plasma TG levels of vldlr-/- mice were 2.5-fold increased compared with those of vldlr+/+ littermates (1.20 +/- 0.37 mM vs. 0.47 +/- 0.18 mM; P < 0.001). Strikingly, an intragastric fat load led to a 9-fold increased postprandial TG response in vldlr-/- compared with vldlr+/+ mice (226 +/- 188 mM/h vs. 25 +/- 11 mM/h; P < 0.05). Accordingly, the plasma clearance of [3H]TG-labeled protein-free chylomicron-mimicking emulsion particles was delayed in vldlr-/- compared with vldlr+/+ mice (half-life of 12.0 +/- 2.6 min vs. 5.5 +/- 0.9 min; P < 0.05), with a 60% decreased uptake of label into adipose tissue (P < 0.05). VLDLr deficiency did not affect the plasma half-life and adipose tissue uptake of albumin-complexed [14C]FFA, indicating that the VLDLr facilitates postprandial LPL-mediated TG hydrolysis rather than mediating FFA uptake. We conclude that the VLDLr plays a major role in the metabolism of postprandial lipoproteins by enhancing LPL-mediated TG hydrolysis.