Pancreatic lipase inhibition

In 1987, scientists at Hoffmann-La Roche described their discovery of hpstatin (5), a secondary metabolite isolated from Strptomyces toxytricini, and demonstrated that it is a potent inhibitor of pancreatic lipase.Simple hydrogenation of 5 formed terahydrolipstatin (1,USAN, orlistat) which possesses comparable biological activity but is more stable than 5. Orlistat (1, Xenical ) works through pancreatic lipase inhibition. Pancreatic lipase is the key enzyme of dietary triglyceride absorption, exerting its activity... 

Orlistat binds to intestinal and pancreatic lipases, inhibiting their action and reduces dietary fat absorption by about 30%. The typical dose of orlistat is 120 mg three times per day with meals. Less than 1% of the drug is taken up. Thus, most of the drug is excreted unchanged in faeces. 

Zheng Q, Li W, Han LK, Koike K (2007) Pancreatic lipase-inhibiting triterpenoid saponins from Gypsophila oldhamiana. Chem Pharm Bull 55 646-650... 

Within the small intestine, bile-acid binding interferes with micelle formation. Nauss et al. [268] reported that, in vitro, chitosan binds bile acid micelles in toto, with consequent reduced assimilation of all micelle components, i.e., bile acids, cholesterol, monoglycerides and fatty acids. Moreover, in vitro, chitosan inhibits pancreatic lipase activity [269]. Dissolved chitosan may further depress the activity of lipases by acting as an alternative substrate [270]. 

Mecfianism of Action A gastric and pancreatic lipase inhibitor that inhibits absorption of dietary fats by inactivating gastric and pancreatic enzymes. Therapeutic Effect Resulting caloric deficit may positively affect weight control. 

Correct answer = A. Pancreatic lipase hydrolyzes dietary triacylglycerol primarily to 2-monoacylglycerol plus two fatty acids. These products of hydrolysis can be absorbed by the intestinal mucosal cells. Bile salts do not inhibit release of fatty acids from triacylglycerol, but rather are necessary for the proper solubilization and hydrolysis of dietary triacylglycerol in the small intestine. Short- and medium-chain length fatty acids enter the portal circulation after absorption from the small intestine. Synthesis of apolipoproteins, especially apo B-48, is essential for the assembly and secretion of chylomicrons. 

Detailed account of kinetics and inhibition of pancreatic lipase action on emulsified triacylglycerol, including special treatment of initial rate measurements and pKa of liberated fatty acids. 

Patton, J.S. and Carey, M.C. 1981. Inhibition of human pancreatic lipase-colipase activity by mixed bile salt-phospholipid micelles. Am. J. Physiol. 241, G328-G336. 

Like pancreatic lipase, this enzyme is clearly dependent on a lipid/water interface for maximal activity, where it also may reach a very high catalytic rale, Abo like pancreatic lipase, it is not inhibited by serine esterase inhibitors like DFP orPMSF. 

Ruff, M. D. Read, C. P. (1973). Inhibition of pancreatic lipase by Hymenolepis diminuta. Journal of Parasitology, 59 105-11. 

Orlistat (Xenical /Roche) is a reversible gastric and pancreatic lipase inhibitor. The compound has no effect on appetite suppression but rather acts by inhibiting dietary fat absorption from the GI tract. Sibutramine (Meridia /Abbott) and its major active metabolites are re-uptake... 

The drug orlistat (Xenical), which is promoted for the treatment of obesity, acts by inhibiting pancreatic lipase, thereby reducing the digestion and absorption of fat in the smaU intestine. 

Orlistat inhibits pancreatic lipase, thus preventing the breakdown of dietary lipids, which reduces their absorption. 

The only known lipase that is nonspecific is the enzyme of a mold. Geotrichum candidum. It has a decided preference for fatty acids with a cis-A9 double bond such as oleic acid 14). There is no explanation for this specificity. The lipases of most other microorganisms are very similar to pancreatic lipase. For example, the lipase of the mold Rhizopus arrhizus is an exoenzyme which contains carbohydrates that are not essential for activity. It is not inhibited by DFP, it is specific for primary ester groups, and it does not distinguish between diflEerent fatty acids (15). Other microbial lipases are similar in these respects but may diflFer in their recognition of steric hindrance. The lipase of Stapyhlococcus aureus... 

Orlistat Inhibits pancreatic lipase, blocks At 1 year of treatment, 51% of the Oily spotting, abdominal pain. 

Lipstatin (58), comprised of a 3,5-dihydroxy-2-hexyl hexadeca-7,9-dienoic acid with cyclization of the hydroxy group at C-3 with the carboxylic acid to form a P-lactone and esterification of the hydroxy group at C-5 with a A-formyl leucine, was isolated from Streptomyces toxytricini. It inhibits gastric and pancreatic lipase and blocks intestinal absorption of lipids (40, 41). Reduction of the olefins led to the synthesis of tetrahydrolipstatin, which was approved in 1999 as Xenical (59) for the treatment of obesity (42-44). 

Orlistat is a pentanoic acid ester that binds to and inhibits gastric and pancreatic lipases the resulting inhibition of their activity prevents the absorption of about 30% of dietary fat compared with a normal 5% loss. Weight loss is due to calorie loss but drug-related adverse effects also contribute by diminishing food intake. The drug is not absorbed from the alimentary tract. 

Pancreatic lipase is one of the mammalian key digestive enzymes. It completes the dietary triacylglycerol breakdown initiated by preduode-nal lipases, including lingual and gastric enzymes, (see below). The enzyme is inhibited in the intestine by bile salts, but the activity is restored in the presence of colipase (CLP), a relatively short (95 residues) heat-stable polypeptide secreted by the pancreas (Semeriva and Desnuelle, 1979 Borgstrbm and Erlanson-Albertsson, 1984). The structural details of the interaction of colipase with lipase are described in Section III,C. 

Orlistat. Orlistat acts in the GI tract, where it inhibits pancreatic lipases located in the lumen. Systemic exposure of the drug is not required for pharmacological activity. With negligible oral bioavailability (F < 5%), orlistat is primarily excreted unchanged in the feces. However, several metabolites including (40) and (41) have been identified in the plasma of both normal and obese volunteers. These compounds are formed by hydrolysis cf both the N-formyl leucine ester moiety and the lactone ring and do not exhibit any inhibitory activities toward pancreatic lipases (68) (see Fig. 15.1). 

Human pancreatic lipase (HPL) alone is inactive in vitro on an emulsified TAG substrate in the presence of supramiceUar concentrations of bile salts such as those found in the small intestine. Bile salts are amphiphilic molecules that bind to the oil-water interface and prevent pancreatic hpase adsorption, and thus hpo-lysis, from occurring [3, 4]. The inhibition by bile salts can, however, be reversed by the specific pancreatic hpase cofactor cohpase [3, 5-7], via the formation of a specific 1 1 hpase-cohpase complex. 

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