Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight.

OBJECTIVE: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. RESEARCH DESIGN AND METHODS: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. RESULTS: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). CONCLUSION: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse.

Two triglyceride lipases, lipoprotein lipase and hepatic triglyceride lipase, participate in the metabolism of plasma lipoproteins. A single recessive mutation, cld, on mouse chromosome 17 causes an apparent deficiency of both lipoprotein lipase and hepatic triglyceride lipase activities. Mice homozygous for this defect develop lethal hyperchylomicronemia within 2 days postpartum as a consequence of nursing. Plasma triglyceride values in affected mice often reach 20,000 milligrams per deciliter (100 times higher than that in normal littermates), and total lipase activity in plasma or tissues is 5 to 20 percent of that in controls.

Skeletal muscle peroxisome proliferator- activated receptor-gamma expression in obesity and non- insulin-dependent diabetes mellitus.

UNLABELLED: The two isoforms of peroxisome proliferator-activated receptor-gamma (PPARgamma1 and PPARgamma2), are ligand-activated transcription factors that are the intracellular targets of a new class of insulin sensitizing agents, the thiazolidinediones. The observation that thiazolidinediones enhance skeletal muscle insulin sensitivity in obesity and in patients with non-insulin-dependent diabetes mellitus (NIDDM), by activating PPARgamma, and possibly by inducing its expression, suggests that PPARgamma expression in skeletal muscle plays a key role in determining tissue sensitivity to insulin, and that PPARgamma expression may be decreased in insulin resistant subjects. We used a sensitive ribonuclease protection assay, that permits simultaneous measurement of the two isoforms, to examine the effects of obesity and NIDDM, and the effects of insulin, on skeletal muscle levels of PPARgamma1 and PPARgamma2 mRNA. We studied seven patients with NIDDM (body mass index, 32+/-1 kg/m2), seven lean (24+/-1 kg/m2), and six obese (36+/-1 kg/m2) normal subjects. Biopsies from the vastus lateralis muscle were taken before and after a 5-h hyperinsulinemic (80 mU/m2 per minute) euglycemic clamp. The obese controls and NIDDM patients were insulin resistant with glucose disposal rates during the last 30 min of the clamp that were 67 and 31%, respectively, of those found in the lean controls. PPARgamma1, but not PPARgamma2 mRNA was detected in skeletal muscle at 10-15% of the level found in adipose tissue. No difference was found in PPARgamma1 levels between the three groups, and there was no change in PPARgamma1 levels after 5 h of hyperinsulinemia. In obese subjects, PPARgamma1 correlated with clamp glucose disposal rates (r = 0.92, P < 0.01). In the lean and NIDDM patients, muscle PPARgamma1 levels correlated with percentage body fat (r = 0.76 and r = 0.82, respectively, both P < 0.05) but not with body mass index. IN CONCLUSION: (a) skeletal muscle PPARgamma1 expression does not differ between normal and diabetic subjects, and is not induced by short-term hyperinsulinemia; (b) skeletal muscle PPARgamma1 expression was higher in subjects whose percent body fat exceeded 25%, and this may be a compensatory phenomenon in an attempt to maintain normal insulin sensitivity.

Lipoprotein metabolism during acute inhibition of hepatic triglyceride lipase in the cynomolgus monkey.

The role of the enzyme hepatic triglyceride lipase was investigated in a primate model, the cynomolgus monkey. Antisera produced against human postheparin hepatic lipase fully inhibited cynomolgus monkey posttheparin plasma hepatic triglyceride lipase activity. Lipoprotein lipase activity was not inhibited by this antisera. Hepatic triglyceride lipase activity in liver biopsies was decreased by 65-90% after intravenous infusion of this antisera into the cynomolgus monkey. After a 3-h infusion of the antisera, analytic ultracentrifugation revealed an increase in mass of very low density lipoproteins (S(f) 20-400). Very low density lipoprotein triglyceride isolated by isopycnic ultracentrifugation increased by 60-300%. Analytic ultracentrifugation revealed an increase in mass of lipoproteins with flotation greater than S(f) 9 (n = 4). The total mass of intermediate density lipoproteins (S(f) 12-20) approximately doubled during the 3 h of in vivo enzyme inhibition. While more rapidly floating low density lipoproteins (S(f) 9-12) increased, the total mass of low density lipoproteins decreased after infusion of the antibodies. The changes in high density lipoproteins did not differ from those in control experiments. In order to determine whether the increases of plasma concentrations of very low density lipoproteins were due to an increase in the rate of synthesis or a decrease in the rate of clearance of these particles, the metabolism of radiolabeled homologous very low density lipoproteins was studied during intravenous infusion of immunoglobulin G prepared from the antisera against hepatic triglyceride lipase (n = 3) or preimmune goat sera (n = 3). Studies performed in the same animals during saline infusion were used as controls for each immunoglobulin infusion. There was a twofold increase in the apparent half-life of the very low density lipoprotein apolipoprotein-B tracer in animals receiving the antibody, consistent with a decreased catabolism of very low density lipoproteins. Concomitantly, the rise in low density lipoprotein apoprotein-B specific activity was markedly delayed. None of these changes were observed during infusion of preimmune immunoglobulin G.Hepatic triglyceride lipase participates with lipoprotein lipase in the hydrolysis of the lipid in very low density lipoproteins, intermediate density lipoproteins, and the larger low density lipoproteins (S(f) 9-12). Thus, hepatic triglyceride lipase appears to function in a parallel role with lipoprotein lipase in the conversion of very low density and intermediate density lipoproteins to low density lipoproteins (S(f) 0-9).

Effect of heparin-induced lipolysis on the distribution of apolipoprotein e among lipoprotein subclasses. Studies with patients deficient in hepatic triglyceride lipase and lipoprotein lipase.

In normal subjects, apolipoprotein E (apo E) is present on very low density lipoproteins (VLDL) (fraction I) and on particles of a size intermediate between VLDL and low density lipoproteins (LDL) (fraction II). The major portion of apo E is, however, on particles smaller than LDL but larger than the average high density lipoproteins (HDL) (fraction III). To investigate the possible role of the vascular lipases in determining this distribution of apo E among the plasma lipoproteins, we studied subjects with primary deficiency of either hepatic lipase or of lipoprotein lipase and compared them with normal subjects. Subjects with familial hepatic triglyceride lipase deficiency (n = 2) differ markedly from normal in that fraction II is the dominant apo E-containing group of lipoproteins. When lipolysis of VLDL was enhanced in these subjects upon release of lipoprotein lipase by intravenous heparin, a shift of the apo E from VLDL into fractions II and III was observed. In contrast, apolipoproteins CII and CIII (apo CII and CIII, respectively) did not accumulate in intermediate-sized particles but were shifted markedly from triglyceride rich lipoproteins to HDL after treatment with heparin. In subjects with primary lipoprotein lipase deficiency (n = 4), apo E was confined to fractions I and III. Release of hepatic triglyceride lipase by heparin injection in these subjects produced a shift of apo E from fraction I to III with no significant increase in fraction II. This movement of apo E from large VLDL and chylomicron-sized particles occurred with little hydrolysis of triglyceride and no significant shift of apo CII or CIII into HDL from triglyceride rich lipoproteins. When both lipoprotein lipase and hepatic triglyceride lipase were released by intravenous heparin injection into normal subjects (n = 3), fraction I declined and the apo E content of fraction III increased by an equivalent amount. Either moderate or no change was noted in the intermediate sized particles (fraction II). These data strongly support the hypothesis that fraction II is the product of the action of lipoprotein lipase upon triglyceride rich lipoproteins and is highly dependent on hepatic triglyceride lipase for its further catabolism. In addition, the hydrolysis by hepatic triglyceride lipase of triglyceride rich lipoproteins in general results in a preferential loss of apo E and its transfer to a specific group of large HDL.

Measurement of lipoprotein lipase and hepatic triacylglycerol lipase in post-heparin plasma of the cynomolgus monkey.

Conditions for measurement of the lipolytic activities, lipoprotein lipase and hepatic triacylglycerol lipase in cynomolgus monkey postheparin plasma are described. The two activities are separable by heparin-Sepharose chromatography. Goat anti-human hepatic triacylglycerol lipase serum inhibits monkey hepatic triacylglycerol lipase activity and allows direct measurement of lipoprotein lipase in post-heparin plasma. While both human and homologous serum can be used as a source of activator apolipoprotein, homologous serum produces a much greater activation.

Accumulation of cholestatic lipoproteins in ANIT-treated human apolipoprotein A-I transgenic rats is diminished through dose-dependent apolipoprotein A-I activation of LCAT.

Administration of alpha-naphthylisothiocyanate (ANIT) to rats induces changes to plasma lipids consistent with cholestasis. We have previously shown (J. Lipid Res. 37 (1996) 1086) that animals treated with ANIT accumulate large amounts of free cholesterol (FC) and phospholipid (PL)-rich cholestatic lipoproteins in the LDL density range by 48 h. This lipid was cleared by 120 h through apparent movement into HDL with concomitant cholesteryl ester (CE) production. It was hypothesised that the clearance was mediated through the movement of the PL and FC into apolipoprotein A-I (apo A-I) containing lipoproteins followed by LCAT esterification to form CE. To test this hypothesis, rats overexpressing various amounts of human apo A-I (TgR[HuAI] rats) were treated with ANIT (100 mg/kg) and the effect of plasma apo A-I concentration on plasma lipids and lipoprotein distribution was examined. In untreated TgR[HuAI] rats, human apo A-I levels were strongly correlated to plasma PL (r(2)=0. 94), FC (r(2)=0.93) and CE (r(2)=0.90), whereas in ANIT-treated TgR[HuAI] rats, human apo A-I levels were most strongly correlated to CE levels (r(2)=0.80) and an increased CE/FC ratio (r(2)=0.62) and the movement of cholestatic lipid in the LDL to HDL. Since LCAT activity was not affected by ANIT treatment, these results demonstrate that the ability of LCAT to esterify the plasma FC present in cholestatic liver disease is limited by in vivo apo A-I activation of the cholestatic lipid and not by the catalytic capacity of LCAT.

Membrane-bound lipoprotein lipase on human monocyte-derived macrophages: localization by immunocolloidal gold technique.

Macrophages from both rodent and human sources have been shown to produce lipoprotein lipase (LPL), the enzyme activity of which can be measured in culture media and in cellular homogenates. The studies reported here show the presence of LPL on the surface of human monocyte-derived macrophages. An inhibitory monoclonal antibody to human LPL was used for cellular and immunoelectron microscopy studies. This antibody is a competitive inhibitor of LPL hydrolysis of triacylglycerol but does not inhibit LPL hydrolysis of a water-soluble substrate, p-nitrophenyl acetate. Furthermore, when postheparin plasma was mixed with monoclonal antibody prior to gel filtration on 6% agarose, the LPL activity eluted with the lipoproteins and was not inhibited by the antibody. These studies suggest that the antibody recognized the lipid/lipoprotein binding site of the LPL molecule. Membrane-bound LPL was demonstrated on human monocyte-derived macrophages using colloidal gold-protein A to detect the monoclonal antibody to LPL. The surface colloidal gold was randomly distributed with a surface density of 56,700 gold particles per cell. Control cells cultured in heparin-containing media (10 units/ml) or cells reacted with anti-hepatic triacylglycerol lipase monoclonal IgG or nonimmune mouse IgG did not exhibit membrane binding of protein A-gold. Macrophages were incubated with control and monoclonal anti-LPL IgGs and 125I-labeled anti-mouse IgG F(ab')2. Heparin-releasable membrane-bound anti-LPL antibody was demonstrated. These studies demonstrate the presence of LPL on the surface of human monocyte-derived macrophages, such that the LPL is oriented with its lipid-binding portion (recognized by this antibody) exposed. Membrane-associated LPL may be important in the interaction and subsequent uptake of lipid and lipoproteins by macrophages and in the generation of atherosclerotic foam cells.

Production and use of an inhibitory monoclonal antibody to human lipoprotein lipase.

Studies were performed to produce a monoclonal antibody to human lipoprotein lipase, verify the specificity of the antibody for lipoprotein lipase, and use this antibody for detection of lipoprotein lipase protein in human post-heparin plasma. Partially purified lipoprotein lipase from human milk was used as an antigen for the production of anti-lipoprotein lipase antibodies in mice. The spleen was removed from the animal having the highest titer of inhibitory antibodies to lipoprotein lipase and the cells were fused mouse myeloma cells. Culture media from the resulting hybridomas were screened for their ability to inhibit lipoprotein lipase catalytic activity. This screening procedure thus identified only those hybridomas which produced antibodies directed against lipoprotein lipase. One monoclonal antibody, from one clone, was selected for detailed study. The specificity of this antibody for lipoprotein lipase protein was established by three methods. First, post-heparin plasma lipoprotein lipase activity and immunoreactivity detected by an enzyme-linked immunosorbent assay (ELISA) co-eluted during heparin-agarose and phenyl-Sepharose chromatography. Second, the antibody detected a protein which was released into the circulation after intravenous injection of heparin into humans. Third, both immunoreactive lipoprotein lipase protein and lipoprotein lipase enzymatic activity were lost by heat-inactivation of lipoprotein lipase. The use of active enzyme as an antigen and the procedure used to screen the monoclonal antibody-producing hybridomas allowed the production of an inhibitory anti-human lipoprotein lipase monoclonal antibody. This antibody is useful for detection of lipoprotein lipase protein in plasma and should allow for immunohistochemical staining of active lipoprotein lipase enzyme in tissues. Moreover, the methods described for screening hybridomas may be modified and used to produce specific antibodies against other partially purified enzymes.

Expression of lipoprotein lipase gene in combined lipase deficiency.

The expression of the gene for lipoprotein lipase (LPL) was studied in brown adipose tissue and the liver of combined lipase deficient (cld/cld) and unaffected mice. The mRNA specific for LPL was detected in both animals. Although the size of LPL mRNA in cld mice was similar to that of unaffected mice, the mRNA concentration in affected animals was higher than in unaffected animals. We also studied the LPL gene mutation in cld mice by Southern blot analysis. No restriction fragment length polymorphisms were observed after digestion with 16 endonucleases. These data indicate that there is no gene insertion or deletion, but do not exclude the possibility of point mutation in the LPL structural gene. However, the present results agree with the hypothesis that the genetic defect in cld is not due to a mutation in the LPL structural gene, but instead involves the defective post-translational processing of LPL or defective cellular function affecting transport and secretion of this enzyme group.

Plasma lipolytic activity. Relationship to postheparin lipolytic activity and evidence for metabolic regulation.

Lipolytic activity was measured in human plasma without prior administration of intravenous heparin. Eluted from heparin-Sepharose in a barbital buffer containing 6 mg/ml heparin, plasma lipolytic activities in 20 subjects were distributed between hepatic triglyceride lipase (HTGL, mean +/- SE 60.6 +/- 4.6%) and extrahepatic lipoprotein lipase (LPL, 39.4 +/- 4.6%). Confirmation of the identities of HTGL and LPL was provided by inhibitory antisera. Preheparin LPL activity was absent in plasma from a patient with type I hyperlipoproteinemia. Both preheparin HTGL and LPL activities correlated with the respective activities measured in plasma obtained 15 min after intravenous injection of heparin (rs = + .774 and + .685, respectively; n = 12). Evidence for the metabolic regulation of preheparin lipases was provided by measurement of significant increases in LPL and HTGL activities after oral glucose ingestion. Overall, preheparin plasma HTGL and LPL activities may reflect ongoing lipoprotein lipolytic activity in tissue beds, and because these measurements do not require the administration of intravenous heparin, they should prove useful for additional studies of short-term regulation of the lipases.

A selective peroxisome proliferator-activated receptor-gamma (PPARgamma) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists such as the thiazolidinediones are insulin sensitizers used in the treatment of type 2 diabetes. These compounds induce adipogenesis in cell culture models and increase weight gain in rodents and humans. We have identified a novel PPARgamma ligand, LG100641, that does not activate PPARgamma but selectively and competitively blocks thiazolidinedione-induced PPARgamma activation and adipocyte conversion. It also antagonizes target gene activation as well as repression in agonist-treated 3T3-L1 adipocytes. This novel PPARgamma antagonist does not block adipocyte differentiation induced by a ligand for the retinoid X receptor (RXR), the heterodimeric partner for PPARgamma, or by a differentiation cocktail containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthine. Surprisingly, LG100641, like the PPARgamma agonist rosiglitazone, increases glucose uptake in 3T3-L1 adipocytes. Such selective PPARgamma antagonists may help determine whether insulin sensitization by thiazolidinediones is mediated solely through PPARgamma activation, and whether there are PPARgamma-ligand-independent pathways for adipocyte differentiation. If selective PPARgamma modulators block adipogenesis in vivo, they may prevent obesity, lower insulin resistance, and delay the onset of type 2 diabetes.

Design and synthesis of 2-methyl-2-[4-(2-[5-methyl-2-aryloxazol-4-yl]ethoxy)phenoxy]propionic acids: a new class of dual PPARalpha/gamma agonists.

Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.

Interaction of lipoprotein lipase with heparin.

The hydrolysis of triglyceride-rich plasma lipoproteins is initiated by lipoprotein lipase (LPL) located at the luminal surface of endothelial cells. We previously reported that LPL binds to cultured endothelial cells with a Km of 2.7 x 10(-7) M and that this binding is inhibited by heparinase, heparin, or heparan sulfate. We and others recently isolated LPL cDNAs from various animals. The deduced amino acid sequence from cDNA sequence is highly conserved among animal species. The structural analysis revealed two regions rich in basic amino acid residues at the carboxyl-terminal region that may interact with the anionic heparin-like molecules. Amino acid residues 292 to 300 of bovine LPL are extremely similar to the reported heparin binding sites on apolipoproteins B-100 (amino acid residues 3359-3367) and E (amino acid residues 142-150).

Very low-density lipoprotein metabolism in an unusual case of lipoatrophic diabetes.

Complete acquired lipoatrophic diabetes (LD) is characterized by nonketotic insulin-resistant diabetes, elevated very low-density lipoprotein (VLDL) triglyceride (TG) levels, and absent subcutaneous fat. We studied a young child in whom LD atypically developed after the onset of type 1 diabetes mellitus. On uncontrolled home diet the patient had triglyceride levels over 1,000 mg/dL on multiple occasions. In order to demonstrate the effects of caloric and dietary-fat restriction on VLDL metabolism, 3H-glycerol and autologous 125I-VLDL were used to quantitate the turnover of VLDL-TG and VLDL-apolipoprotein B (apo B) during two periods of caloric restriction. Consumption of a 900-kcal 40-g fat diet resulted in a plasma triglyceride level of 1383 mg/dL (ten-fold elevation). This hypertriglyceridemia was associated with markedly increased production rates of both VLDL-TG (73.7 mg/kg/h) and VLDL-apo B (126.9 mg/kg/d). Consumption of a 900-kcal 25-g fat diet resulted in a plasma TG level of 663 mg/dL. This reduction in plasma TG was associated with a 40% decrease in VLDL-TG production rate (PR) (45.1 mg/kg/h). There was no change in the production rate (PR) of VLDL-apo B. The hypertriglyceridemia in this patient was due to marked over production of VLDL. Furthermore, the studies demonstrate: (1) the independent benefits of caloric and dietary-fat restriction in the treatment of LD, and (2) that fat restriction lowered plasma triglyceride by its effect on the VLDL-TG production rate.

Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat.

Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues.

Plasma lipoprotein abnormalities associated with acquired hepatic triglyceride lipase deficiency.

Two enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are released into human plasma after intravenous injection of heparin. LPL is the major enzyme responsible for initiating catabolism of chylomicrons and very-low-density lipoproteins (VLDL). The physiological role of HTGL is less certain. HTGL has been postulated to be an alternate enzyme to LPL in hydrolysis of triglyceride in VLDL and to be an important enzyme for removal of phospholipid from both low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In this latter role, this enzyme would convert larger, lighter lipoprotein particles to smaller denser particles. HTGL deficiency has been found in severe liver disease and with a genetic deficiency of this enzyme. A unique patient is described with acquired hepatic triglyceride lipase deficiency and vitamin A intoxication. This patient developed hypercholesterolemia with an increase in both LDL and HDL. An increased proportion of lighter LDL (LDL1) and HDL (HDL2) was noted. In addition, after administration of heparin there was no shift in the distribution of apoE in plasma fractionated using a column containing 4% agarose. These findings are consistent with a postulated role of HTGL in metabolism of light LDL and HDL particles and some classes of apoE containing lipoproteins.

Transient lipoprotein lipase deficiency with hyperchylomicronemia.

Type I hyperlipoproteinemia is a rare disorder characterized by the presence of chylomicrons in fasting plasma and dysfunction of the lipoprotein lipase system. The disease may result from primary genetic defects leading to the lack of the enzyme lipoprotein lipase or to a deficiency in the CII apoprotein activator of that enzyme. It may also appear secondary to underlying systemic diseases. We now describe a case of hyperchylomicronemia and pancreatitis with a lack of lipoprotein lipase activity as assessed by three different methods. The patient had no evidence of a plasma inactivator of lipoprotein lipase, and his plasma was able to activate the enzyme in control postheparin plasma. The postheparin plasma hepatic triglyceride lipase was normal. Tests for associated systemic diseases were negative. Six weeks after presentation, that patient's lipoprotein levels and postheparin plasma lipase activities were normal. This was a unique case of hyperchylomicronemia which for a limited time was indistinguishable from primary lipoprotein lipase deficiency by current biochemical techniques.