Effects of tetrahydrolipstatin, a lipase inhibitor, on absorption of fat from the intestine of the rat.
Tetrahydrolipstatin (THL) derived by hydrogenation from lipstatin, a lipase inhibitor produced by Streptomyces toxytricini, has been shown to inhibit in vitro the activity of all three lipases secreted to the gastro-intestinal tract; gastric lipase, pancreatic lipase and carboxylester lipase (cholesterol ester hydrolase). The effects of THL on intestinal absorption of fat (transport to the thoracic duct chyle) has now been investigated after intraduodenal infusion in a rat model. Absorption of label from oleic acid when administered with monoolein in micellar bile salt solution was not affected by THL in concentrations up to 10(-4) M calculated on the volume of the aqueous phase. Absorption of free cholesterol in micellar bile salt solution of the lipolytic products of triolein; oleic acid and monoolein, is not significantly affected at a concentration of THL of 10(-4) M. Absorption of cholesterol from cholesteryl oleate under the same conditions is almost completely inhibited. The results indicate that absorption of free cholesterol is not dependent on the activity of pancreatic cholesterol ester hydrolase. The absorption of emulsified triolein was not significantly affected by 10(-5) M THL but decreased to around 30% of the controls by a concentration 10-times higher. There was no significant decrease of cholesterol absorption when administered in emulsified triolein while absorption of cholesteryl oleate was reduced at both concentrations of THL and almost completely at 10(-4) M. Radioactivity from [2-14C]THL when administered emulsified in triolein was recovered in urine, bile and thoracic duct lymph to 10-14, 8-13 and 1-3%, respectively, largely independent on dose administered. Label from [1"-14C] THL was recovered in the same amounts in lymph but much less in bile and urine indicating that the amino acid moiety has been split off early in the absorption process.
Fernandez
E
E
Department of Physiological Chemistry, University of Lund, Sweden.
Borgström
B
B
D000818:Animals; D002784:Cholesterol / Q000493:pharmacokinetics; D002788:Cholesterol Esters / Q000493:pharmacokinetics; D004041:Dietary Fats / Q000493:pharmacokinetics*; D004655:Emulsions / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects*; D007783:Lactones / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors; D008297:Male; D008823:Micelles; D019301:Oleic Acid; D009829:Oleic Acids / Q000493:pharmacokinetics; D000077403:Orlistat; D051381:Rats; D011919:Rats, Inbred Strains
D002788:Cholesterol Esters; D004041:Dietary Fats; D004655:Emulsions; D007783:Lactones; D008823:Micelles; D009829:Oleic Acids; D019301:Oleic Acid; C014409:cholesteryl oleate; D000077403:Orlistat; D002784:Cholesterol; D008049:Lipase