Disease relevance of Tetrahydrolipstatin

• OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years [1].
• Orlistat, a Food and Drug Administration-approved drug used for treating obesity, was included in this screen [2].
• Orlistat is equally effective as phototherapy for the treatment of unconjugated hyperbilirubinemia in Gunn rats, and combined oral treatment with Orl + CaP is more effective than phototherapy [3].
• In the long term, orlistat has been shown to be more effective than placebo in reducing body weight and serum total and low-density lipoprotein cholesterol levels [4].
• Orlistat-induced cutaneous leukocytoclastic vasculitis [5].

Psychiatry related information on Tetrahydrolipstatin

• After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032) [6].
• All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months [7].
• Evidence on longer-term benefits of orlistat (>2 years) will be of importance for future decision-making [8].
• The overall Eating Disorder Inventory 2 score at week 24 was significantly lower in patients treated with orlistat than in those in the placebo group (p = 0.011) [9].
• Weight reduction by means of life-style changes, supported by medical interventions with inhibitors of intestinal fat absorption (e.g. Orlistat) or appetite suppressants (e.g. Sibutramine), is essential in order to decrease the risk of atherosclerosis [10].

High impact information on Tetrahydrolipstatin

• CONCLUSIONS: Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors [1].
• Density gradient analysis revealed that most of the secreted heart lipoproteins were LDLs, even when the labeling experiments were performed in the presence of tetrahydrolipstatin, an inhibitor of lipoprotein lipase [11].
• During distentions, intragastric volumes were greater during infusion of LCT and MCT than during the respective THL conditions or SPE, but plasma CCK levels did not change [12].
• Increasing doses of tetrahydrolipstatin induced a dose-dependent inhibition of duodenal lipase activity (P < 0.01); 120 mg tetrahydrolipstatin eliminated the postprandial lipase peak activity, free fatty acid levels decreased to < 5% of total fatty acids, and plasma cholecystokinin levels were suppressed by 77% (P < 0.01) [13].
• METHODS: Fat hydrolysis was inhibited by intraduodenal perfusion of tetrahydrolipstatin, an irreversible lipase inhibitor [13].

Chemical compound and disease context of Tetrahydrolipstatin

• Along with weight loss, orlistat also favourably affects blood pressure and glucose and insulin levels in obese individuals and in obese type 2 diabetic patients [4].
• Weight loss attributable to obesity pharmacotherapy (ie, in excess of placebo) in trials lasting 36 to 52 weeks was 8.1% or 7.9 kg for those receiving phentermine resin, 5.0 % or 4.3 kg for those receiving sibutramine hydrochloride, 3.4% or 3.4 kg for those receiving orlistat, and -1.5% or -1.5 kg for those receiving diethylpropion hydrochloride [14].
• Treatment of M. kansasii with either isoniazid (INH), a well-known type II fatty acid synthase (FAS-II) and mycolic acid biosynthesis inhibitor, or tetrahydrolipstatin (THL), a drug approved for treating obesity, correlated with a reduced incorporation of [(14)C]-acetate into both mycolic acids and MMDAG [15].
• In the United States, only sibutramine and orlistat are available for the long-term treatment of obesity [16].
• A total of 12 healthy adult volunteers within 20% of their ideal body weight entered a 7-day run-in diet period before being randomized to orlistat (120 mg) or chitosan (890 mg) three times daily for 7 days [17].

Biological context of Tetrahydrolipstatin

• By virtue of its ability to inhibit fatty acid synthase, Orlistat halts tumor cell proliferation, induces tumor cell apoptosis, and inhibits the growth of PC-3 tumors in nude mice [2].
• Lipolysis and diglyceride lipase activity in islets are abolished by orlistat, a pan-lipase inhibitor [18].
• 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 [19].
• LPL significantly suppressed TNF-alpha-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase [20].
• RESULTS: Orlistat inhibited almost completely (by 75%) lipase activity and accelerated gastric emptying of both the solid (by 52%) and fat (by 44%) phases of the mixed meal (p<0.03) [21].

Anatomical context of Tetrahydrolipstatin

• Role of lipase in the regulation of postprandial gastric acid secretion and emptying of fat in humans: a study with orlistat, a highly specific lipase inhibitor [21].
• A decrease in fat absorption by orlistat appears to favorably influence the ratio between intraabdominal and subcutaneous fat, which suggests that exogenous fat or its composition influences fat distribution [22].
• Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women [22].
• The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration [23].
• Inhibition of LPL activity with tetrahydrolipstatin, a lipase active-site inhibitor, did not affect the LPL-mediated monocyte binding [24].

Associations of Tetrahydrolipstatin with other chemical compounds

• Irrespective of dietary fat content, 3 weeks of combined treatment (Orl + CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided [3].
• The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase [25].
• LpL-mediated LDL selective uptake was not affected by the LpL inhibitor tetrahydrolipstatin but was nearly abolished by heparin, monoclonal anti-LpL antibodies, or chlorate treatment of cells and was not found using proteoglycan-deficient Chinese hamster ovary cells [26].
• In the first 60 min after the meal blood glucose (p=0.001) and plasma insulin (p=0.01) concentrations were higher in patients who had taken orlistat; between 60 and 180 min plasma GLP-1 (p=0.02) concentrations were lower after orlistat than without orlistat [27].
• The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS) [7].
• Plasma levels of CCK (by approximately 53%), PYY (by approximately 40%), and GLP-1 (by approximately 20%) were significantly lowered by Orlistat (P < 0.001), whereas ghrelin levels were unaffected by Orlistat treatment (P = 0.18) [28].

Gene context of Tetrahydrolipstatin

• Inhibition of the enzymic activity with tetrahydrolipstatin (THL) significantly enhanced the effect of EDL, as reflected by a 5.2-fold increase in binding, a 2.6-fold increase in particle uptake and a 1.1-fold increase in CE selective uptake compared with incubations without THL [29].
• Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression [30].
• This increase in selective CE uptake was observed in the presence of tetrahydrolipstatin, an inhibitor of the catalytically active site of HL, suggesting that this HL effect is independent from lipolysis [31].
• LPL-dependent selective alphaTocH uptake was unaffected by the lipase inhibitor tetrahydrolipstatin but was substantially inhibited in cells where proteoglycan sulfation was inhibited by treatment with NaClO(3) [32].
• Orlistat augments postprandial increases in glucagon-like peptide 1 in obese type 2 diabetic patients [33].

Analytical, diagnostic and therapeutic context of Tetrahydrolipstatin

• METHODS: In a double-blind study, 15 healthy subjects were studied on 5 occasions during which LCT or MCT emulsions (2 kcal/min), with or without 120 mg tetrahydrolipstatin (THL, lipase inhibitor), or sucrose polyester (SPE, nondigestible fat) were infused intraduodenally in randomized order [12].
• Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (-34% and -28%, respectively); the combination of both was more effective than either treatment alone (-48%; P < .001) [3].
• METHODS: Obese patients with diabetes (n = 33) and obese nondiabetic patients (n = 27) were given orlistat, 120 mg 3 times daily, without a concomitant hypocaloric diet for 6 months (body mass index [calculated as weight in kilograms divided by the square of height in meter; kg/m2] range, 27.8-47.4) [34].
• In a two way cross over study with two test periods of five days, separated by at least 14 days, orlistat 120 mg three times daily or placebo was given with standardised daily meals [21].
• They did this on two separate occasions, with and without 120 mg orlistat, and while in the seated position with their back against a gamma camera [27].

References