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PubMed1975

Ovine pancreatic lipase : purification and some properties.

Lipase has been isolated from sheep pancreas. The lipoprotein complex formed in pancreas homogenates by the enzyme and endogenous lipids is split by treatment with acetone. Lipase is further purified by ion-exchange chromatography and gel filtration. The molecular weight and the amino-acid composition of ovine lipase are very similar to that of the porcine and bovine enzymes. As previously found in bovine lipase, no carbohydrate is covalently bound to the polypeptide chain which has a N-terminal residue of lysine. The study of the catalytic properties of ovine pancreatic lipase indicates that the enzyme is fully activated by colipase from various species in the presence of conjugated bile salt micellar solutions.

Amino Acids↗
PubMed1977

Lipolytic activities against trioctanoin and monoolein in rat intestinal mucosa.

The hydrolysis of trioctanoin and of monoolein by rat intestinal homogenates, catalyzed by the previously described "trioctanoin hydrolase" and "monoglyceride lipase" [Ref. 6 and 11], was shown to be entirely due to the action of the intestinal glycerol-ester hydrolase [Ref. 1 and 2] and to contaminating pancreatic lipase firmly bound to the intestinal cells. These conclusions are supported by experiments based on the chromatographic behaviour of the different lipolytic activities, the use of an immunoserum directed against rat pancreatic juice and the relief of bile salt inhibitions by pancreatic colipase. The results are in favour of the existence of a single lipolytic enzyme in the rat intestinal mucosa, i.e. glycerol-ester hydrolase, active against short- and medium chain mono-, di- and triglycerides and against long chain monoglycerides.

Animals↗
PubMed1999

Enzymatic degradation of SLN-effect of surfactant and surfactant mixtures.

Solid lipid nanoparticles (SLN) show different degradation velocities by the lipolytic enzyme pancreatic lipase as a function of their composition (lipid matrix, stabilizing surfactant). In combination with pancreatic colipase a degradation assay has been developed for studying the degradation behavior. As a measure to follow the degradation the formed free fatty acids have been analyzed using an enzymatic test. In the studies SLN degradation showed dependencies in relation to the length of the fatty acid chains in the triglycerides and the surfactants used for SLN production. The longer the fatty acid chains in the glycerides, the slower the degradation. The influence of surfactants can be degradation accelerating (e.g. cholic acid sodium salt) or a hindering, degradation slowing down effect due to steric stabilization (e.g. Poloxamer 407). As a second steric stabilizer, Tween 80 has been used and the results showed a less pronounced effect on hindering the degradation process than for Poloxamer 407. This result seems to be correlated to the number of ethyleneoxide chains in the molecule. The longer the ethyleneoxide chains are in the molecule, the more hindered is the anchoring of the lipase/colipase complex and consequently the degradation of the SLN. The result can be used to adjust degradation of SLN and consequently drug release in a controlled way.

Biodegradation, Environmental↗
PubMed2000

Egg yolk lipoproteins as substrates for lipases.

Egg yolk emulsions containing phospholipids (about 31%, w/w) are classically used as substrates for measuring phospholipase A2 activity using the pH-stat method. Here we investigated the susceptibility of egg yolk lipoproteins to lipolysis by various highly purified lipases of animal or microbial origin. Egg yolk lipoproteins, which contain up to 65% triacylglycerols, were found to be effective substrates for all the lipases tested. The specific activities measured on egg yolk lipoproteins using the pH-stat technique were found to be 8000, 1000, 1250 and 1700 U/mg in the case of human pancreatic lipase, horse pancreatic lipase, porcine pancreatic lipase and Humicola lanuginosa lipase, respectively. No activity was detected in the absence of colipase with any of the pancreatic lipases tested. Consequently, the classical egg yolk assay cannot be considered as a specific phospholipase A2 assay.

Animals↗
PubMed2000

Afferent signals regulating food intake.

Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. beta-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

Adipose Tissue↗
PubMed1989

Enzymatic and physical characterization of diacylglycerol-phosphatidylcholine interactions in bilayers and monolayers.

The miscibility of 1,3-dioleoylglycerol (DOG) with 1-stearoyl-2-oleoylphosphatidylcholine (SOPC) and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) dispersed in excess buffer was characterized by physical and enzymatic methods. Thermograms for all SOPC-DOG mixtures exhibit a transition at 5.3 degrees C. Above 0.25 mole fraction of DOG, metastability is observed; after the first scan, a second peak appears at 23.4 degrees C which corresponds to the chain melting of pure DOG. This suggests that a complex or preferred packing array is formed which has a DOG mole fraction of 0.25 (XC). Bilayer morphology is maintained in the metastable state up to 0.8 mole fraction of DOG. Above 0.8, a novel, nonlamellar phase is formed. Fluorescence polarization of 1,6-diphenylhexatriene shows that, relative to SOPC alone, there is little change in the order of the acyl chains up to Xc followed by a large decrease above Xc. Similar results were obtained using POPC. Miscibility was also studied in lipid films at the argon-buffer interface. Isothermal phase diagrams for the mixtures at 15 and 24 degrees C exhibited phosphatidylcholine-DOG complex formation, a region of phosphatidylcholine and complex coexistence, and a region of complex and DOG miscibility. The mole fractions of DOG in the complex (Xc) range from 0.24 to 0.27. Porcine pancreatic phospholipase A2 and pancreatic lipase plus colipase were used as probes of the surface in both the monolayer and bilayer systems. In both systems and with both enzymes, substrate hydrolysis increased abruptly with increasing DOG.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorimetry, Differential Scanning↗
PubMed1989

The role of calcium ions and bile salts on the pancreatic lipase-catalyzed hydrolysis of triglyceride emulsions stabilized with lecithin.

Lecithin-stabilized triglyceride emulsions are subject to hydrolysis by pancreatic lipase. The time profiles of these reactions are characterized by a lag-phase and a zero-order phase. Lag phases are more pronounced with long-chain triglycerides. Ca2+ is effective in reducing the lag-phase and activating lipase. Kinetic analysis of the reactions suggests that, like previous findings by others, taurodeoxycholate (TDC) micellar solutions combine with the lipase-colipase complex to form another catalytically active enzyme form. This enzyme form exhibits reduced activity in the absence of Ca2+. In the presence of Ca2+ the mixed micelle-lipase complex becomes more active and opens a new pathway for lipolysis. It is suggested that this enzyme form can bind more easily to interfaces with different physicochemical properties. Under these conditions, Ca2+ activates the lipolysis of short-, medium-, and long-chain triglycerides by a similar mechanism. Maximum activities were measured in the presence of approximately 6 mM TDC and 30 mM Ca2+. The experimental conditions approximate the physiological conditions in the gastrointestinal tract since all of the factors studied here have been reported to be necessary for in vivo lipolysis and/or absorption of triglycerides. A mechanistic model for lipolysis in the presence of Ca2+ and the bile salt TDC is proposed which accounts for most of the experimental observations in a quantitative manner.

Bile Acids and Salts↗
PubMed2002

Fluorimetric analysis of lipase hydrolysis of intermediate- and long-chain glycerides.

For the purpose of deducing the digestive behavior of dietary fat in the digestive organs, a fluorimetric method for the measurement of hydrolysis by porcine pancreatic lipase was performed using intermediate- and long- acyl chain glycerides as substrates. Insoluble glycerides constituted by C10-C16 acyl chains were mechanically dispersed in 100% buffer and hydrolyzed by porcine pancreatic lipase. After the reaction, fatty acid released by the enzyme was extracted and its carboxyl group was fluorescently labeled with 9-bromomethylacridine. The 9-acridinylmethyl derivative of the fatty acid was separated and determined by HPLC. The sensitivity of this method was about 1000 times higher than that of the titrimetric method. Only 0.5 ng of porcine pancreatic lipase was sufficient for one routine assay. This assay method was successfully applied to investigate the enzymatic properties of porcine pancreatic lipase with respect to dietary lipids. The effects of some physiological factors concerned with lipid digestion, such as bile salt and colipase, on the lipase hydrolysis were also examined. The method established in the present study could contribute to a highly sensitive assay of some hydrolases containing lipase with regard to insoluble substrates.

Animals↗
PubMed2002

Degree of in vivo inhibition of human gastric and pancreatic lipases by Orlistat (Tetrahydrolipstatin, THL) in the stomach and small intestine.

BACKGROUND AND AIMS: Orlistat, a lipase inhibitor, strongly inhibits the activities of all gastric/pancreatic lipases except pancreatic phospholipase A(2)in vitro. In clinical use, for obesity treatment, it induces a variable degree of weight loss and steatorrhoéa. The aim of this study was to examine the degree of in vivo inhibition of individual gastric/pancreatic lipases by Orlistat in man, when given as a capsule or mixed into a test meal in the form of an optimal substrate for the lipases. METHODS: Twelve male volunteers were intubated twice with a triple lumen nasal-gastric-duodenal tube and were given a balanced test meal with or without 60 mg Orlistat. Three conditions were compared: (a) Orlistat given as a capsule with the meal, (b) Orlistat mixed into the test meal before ingestion, and (c) test meal without Orlistat. Samples were collected at six 30 min intervals, from stomach, mid-duodenum, and ligament of TreitY. Activities and immune-reactive masses of gastric lipase, pancreatic lipase, carboxyl ester lipase, colipase, and mass of non-polar lipid classes were determined. RESULTS: In vivo effects on the enzyme activities were more pronounced when Orlistat was mixed with the meal than when given as a capsule (7%, 10%, 1% vs 49%, 54%, 34% of normal activity), respectively. Despite efficient inhibition of the lipases, an extensive hydrolysis of the emulsified lipids of the test meal occurred. Orlistat did not affect the immune-reactive amounts of lipases. CONCLUSIONS: Orlistat causes a pronounced in vivo inhibition of gastric and pancreatic lipases in humans. The mixing with the substrate and the fact that little residual lipase activity is necessary to hydrolyse optimally emulsified lipids are likely to be limiting factors for the effect of the drug in clinical practice.

Adult↗
PubMed1995

Human pancreatic lipase. Importance of the hinge region between the two domains, as revealed by monoclonal antibodies.

Several monoclonal antibodies (mAbs) were prepared against human pancreatic lipase (HPL). Two enzyme-linked immunosorbent assay (ELISA) procedures were set up for screening hybridomas producing specific antibodies. Four mAbs (81-23, 146-40, 315-25, and 320-24) of the IgG1 isotype were found to react with HPL in both simple sandwich and double sandwich ELISAs, while mAb 248-31, of the IgG2b isotype, reacted only with HPL in a double sandwich ELISA. The results of Western blot analysis carried out with native and SDS-denatured HPLs indicated that mAb 248-31 recognized only native HPL, while all the other mAbs recognized both forms of HPL. Since mAb 248-31 did not recognize SDS-denatured HPL, it was not possible to localize its epitope. To carry out epitope mapping along the primary sequence of HPL, four fragments (14, 26, 30, and 36 kDa) resulting from a limited chymotryptic cleavage of HPL were characterized by Western blotting as well as N-terminal amino acid sequence analysis. Of the above five anti-HPL mAbs, four (81-23, 248-31, 315-25, and 320-24) were found to inhibit the lipolytic activity of HPL (in both the presence and absence of bile salts and colipase), while mAb 146-40 had no inhibitory effects. The epitope recognized by mAb 146-40 was found to be located in the N-terminal domain (Lys1-Phe335). Combined immunoinactivation and epitope mapping studies showed that three inhibitory mAbs (81-23, 315-25, and 320-24) recognize overlapping epitopes from the hinge region between the N- and C-terminal domains of HPL, belonging to the 26-kDa fragment. In the presence of lipids, a significant decrease has been observed in the bending angle between the N- and C-terminal domains of the HPL tertiary structure (van Tilbeurgh, H., Egloff, M. P., Martinez, C., Rugani, N., Verger, R. and Cambillau, C. (1993) Nature 362, 814-820). From the present immunochemical data, we further propose that locking the hinge movement with mAbs may induce lipase immunoinactivation.

Animals↗
PubMed1998

Structure and activity of rat pancreatic lipase-related protein 2.

The pancreas expresses several members of the lipase gene family including pancreatic triglyceride lipase (PTL) and two homologous proteins, pancreatic lipase-related proteins 1 and 2 (PLRP1 and PLRP2). Despite their similar amino acid sequences, PTL, PLRP1, and PLRP2 differ in important kinetic properties. PLRP1 has no known activity. PTL and PLRP2 differ in substrate specificity, bile acid inhibition, colipase requirement, and interfacial activation. To begin understanding the structural explanations for these functional differences, we solved the crystal structure of rat (r)PLRP2 and further characterized its kinetic properties. The 1.8 A structure of rPLRP2, like the tertiary structure of human PTL, has a globular N-terminal domain and a beta-sandwich C-terminal domain. The lid domain occupied the closed position, suggesting that rPLRP2 should show interfacial activation. When we reexamined this issue with tripropionin as substrate, rPLRP2 exhibited interfacial activation. Because the active site topology of rPLRP2 resembled that of human PTL, we predicted and demonstrated that the lipase inhibitors E600 and tetrahydrolipstatin inhibit rPLRP2. Although PTL and rPLRP2 have similar active sites, rPLRP2 has a broader substrate specificity that we confirmed using a monolayer technique. With this assay, we showed for the first time that rPLRP2 prefers phosphatidylglycerol and ethanolamine over phosphatidylcholine. In summary, we confirmed and extended the observation that PLRP2 lipases have a broader substrate specificity than PTL, we demonstrated that PLRP2 lipases show interfacial activation, and we solved the first crystal structure of a PLRP2 lipase that contains a lid domain.

Amino Acid Sequence↗
PubMed2003

Effect of lipid excipients on in vitro pancreatic lipase activity.

PURPOSE: To study the effects of two lipid excipients, Peceol and Gelucire 44/14 on the in vitro pancreatic lipase activity. METHODS: A 50 microL reaction mixture, consisting of 45 microL (3H) triolein as the radiolabeled substrate, 2.5 microL Peceol or Gelucire 44/14 (0.05-0.5%), either alone or in combination, 2.5 microL colipase (100 microg/mL), and 2.5 microL pancreatic lipase (1 mg/mL), was incubated for 10 min at room temperature. At the end of incubation, the reaction was stopped by the addition of an extraction solvent containing chloroform, methanol, and n-heptane (12.5:14:10), and the mixture vortexed briefly. Subsequently, 250 microL of 50 mM sodium carbonate was added and the aqueous and organic phase separated by centrifugation for 5 min at 1000 g. One hundred microliters of the supernatant was transferred to a scintillation counter and then radioactivity measured after the addition of 3.6 mL of scintillation fluid. Pancreatic lipase activity was determined by measuring the amount of free fatty acid released into the incubation medium and expressed as micromol free fatty acid released/min. RESULTS: When used alone, Peceol inhibited the pancreatic lipase activity significantly in a concentration-dependent manner, with a maximum inhibition of 57% at 0.4% of the excipient [p < 0.05, one-way analysis of variance (ANOVA)]. Similarly, Gelucire 44/14 alone caused inhibition of lipase activity in a concentration-dependent manner. However, the maximum inhibition (30%) was smaller in magnitude compared with the former agent. When the two excipients were used in combination, the inhibitory effects on the enzyme activity were similar to those observed with the individual agents (p < 0.05, one-way ANOVA). However, the maximum inhibition of 30% was lower than that observed with Peceol alone. CONCLUSIONS: The results from this study suggest that these lipid excipients inhibit in vitro pancreatic lipase activity and should be taken into consideration when developing oral formulations using these agents.

Excipients↗
PubMed1987

Human serum pancreatic lipase and trypsin 1 in aging: enzymatic and immunoenzymatic assays.

Two major human pancreatic proteins, lipase and trypsin I, were measured in human sera from 35 elderly healthy adults and 51 young healthy adults. Lipase enzymatic activity was determined by a turbidimetric assay in the presence of colipase; lipase immunoreactive protein and trypsin immunoreactive protein were measured by using immunoenzymatic assays. Serum levels of the pancreatic enzymes were similar in young and elderly adults, with no significant differences between the groups for any of the assays. There was a close correlation between lipase enzyme activity and immunoreactivity in all participants, suggesting that the catalytic activity of lipase was not affected by aging. There were also significant correlations between the levels of immunoreactive lipase protein and immunoreactive trypsin protein, within and between the two groups, suggesting an age-independent relationship between these two pancreatic enzymes.

Adult↗
PubMed1985

Digestion and absorption of lipids in poultry.

Ingested lipids undergo intestinal emulsification, digestion, micellar solubilization, cell membrane permeation, intracellular esterification and incorporation into lipoproteins before release to the interstitial fluid. Bile salts secretion, essential to both emulsification and micelle formation in the intestine, has been found to be influenced by quantity and quality of dietary lipids and by other emulsifiers. Modifications of dietary lipid contents cause changes in pancreatic lipase content and secretion. Colipase secretion by the pancreas seems dependent on both lipid and protein intakes. Intracellular processes essential for lipid absorption increases in rate as lipid intake increases. Bile salts seem to play important roles as moderators of these processes. The ability to digest lipids is not fully developed in the newly hatched poultry. Addition of bile salts, lipase or phospholipids to chick diets improves the digestibility of animal fats, demonstrating that lipid digestive processes are not fully functional in the very young. Physiological studies support these indications. Lipase concentration in pancreatic tissue and intestinal contents of poultry increases several-fold during the first few weeks after hatch. Similar changes with age have been observed in bile salt secretion. The development in enterocytes of fatty acid-binding protein activity seems to parallel the development in lipase activity and bile salt secretion in poultry.

Absorption↗
PubMed1987

Beneficial effect of wheat germ on circulating lipoproteins and tissue lipids in rats fed a high fat, cholesterol-containing diet.

Adult male rats were fed for 7 wk either a low fat diet (3% fat) or a high fat-cholesterol diet (20% fat, 0.5% cholesterol) containing 7% wheat germ or not. Body weights and food intakes were unchanged by adding wheat germ to the control low fat or high fat diets. Adding wheat germ to the high fat-cholesterol diet significantly increased high density lipoprotein (HDL) cholesterol and the HDL-serum cholesterol ratio and lowered the very low density lipoprotein (VLDL) triglycerides. Thus the lipoprotein pattern was comparable to that obtained with the low fat diet, but the VLDL lipid composition remained altered. At the same time, triglyceride and cholesterol accumulation in the liver and the triglyceride content in skin were significantly decreased. When wheat germ was added to the low fat diet, cholesterol and triglycerides were not significantly modified. No adaptative change in lipase and colipase contents was observed in the pancreas of rats fed the wheat germ-supplemented diets, whereas the high fat diet increased these values. The results show a beneficial effect of wheat germ added to a high fat-cholesterol diet on the lipid status of rats; the implicated mechanisms are yet to be elucidated.

Animals↗
PubMed1993

Corandomization of fats improves absorption in rats.

Human milk fat is well absorbed despite its large concentration of long-chain saturated fatty acids (LCSFA), particularly palmitic acid. The superior absorption has been ascribed in part to the uncommonly high proportion of the palmitic acid in the sn-2 position of the triglycerides, 70% in human milk triglycerides compared with 10-15% in the fats and oils commonly used in infant formula blends. Colipase-dependent pancreatic lipase selectively hydrolyzes the fatty acids at the sn-1 and 3 positions, yielding free fatty acids and the 2-monoglyceride, which are absorbable. Free palmitic acid, but not monopalmitin, can be lost as calcium soaps in the feces. The present study demonstrated that mixtures of coconut oil and palm olein are better absorbed by rats if the proportion of LCSFA in the sn-2 position is increased by the process of chemical randomization, in which the fatty acids of the native oils are redistributed equally to all three positions in the rearranged triglycerides. The fecal excretion of total fatty acids, essentially LCSFA, from the mixtures in which the oils were randomized together (corandomized) was 30 to 60% less than from the mixtures of native oils.

Animals↗
PubMedDate not supplied

Pancreatic function testing in meconium disease in CF: two case reports.

We report two infants with cystic fibrosis (CF), presenting with meconium ileus and meconium plug, who had no clinical or biochemical evidence of pancreatic insufficiency during infancy. They underwent pancreatic secretory function testing at 11 and 9 months of age, respectively. Both patients had sufficient lipase and colipase secretion to maintain normal digestion of fat, confirming that meconium disease in CF does not necessarily imply pancreatic insufficiency and the need for enzyme supplementation in infancy. Nonetheless, we documented markedly reduced enzyme secretion in both patients, implying a potential role for the pancreas in the pathogenesis of meconium disease, even when clinical pancreatic insufficiency is absent. In addition, our patient with meconium ileus had a severely limited fluid secretory capacity (10.3% of mean normal values). In contrast, the patient with the milder presentation of meconium plug had a far greater ability to secrete fluid (75% of mean normal), but had poorer pancreatic proteolytic activity. We suggest that impaired fluid secretion may be a very significant factor in the pathogenesis of meconium ileus, and we speculate that an inability to maintain sufficient intraluminal fluid relative to the degree of pancreatic proteolytic deficiency may more adequately explain the risk of occurrence and the severity of intestinal obstruction in CF than either factor alone.

Age Factors↗
PubMed1988

Digestive and absorptive phase anomalies associated with the exocrine pancreatic insufficiency of cystic fibrosis.

The pancreas has an enormous reserve capacity, and significant malabsorption usually signals complete absence of exocrine function. However, there is evidence that acid lipases of nonpancreatic origin play an important compensatory role. Complete duodenal hydrolysis of fat requires a series of complex interdependent physicochemical events involving pancreatic lipase, colipase, phospholipase A2, and bile salts in an environment where the pH must be close to neutrality. Lipolytic products must then be shuttled through the unstirred water layer to the surface of the microvillus membrane by ionized bile salts, which must be present in sufficient concentrations to form micelles. In pancreatic insufficiency, there is not only a defective lipolytic phase but also an impaired micellar phase. The output of bile salts is decreased because of increased fecal loss. Furthermore, a significant percentage of bile salts precipitate because the duodenum is acidic and there is a large predominance of glycine conjugates. Although much less work has been done on the absorptive phase of patients with pancreatic insufficiency, there is tentative evidence that defective phospholipid absorption, essential fatty acid deficiency, and protein malnutrition could impair the absorptive phase, particularly chylomicron formation. Although significant advances have been made in our understanding of factors responsible for malabsorption associated with pancreatic insufficiency, much remains to be done for the further delineation of defects. It is hoped that this will lead to further refinements of enzyme preparations and to new strategies of intervention.

Cystic Fibrosis↗