NDLI: Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial

Content Provider	Springer Nature : BioMed Central
Author	Velliquette, Rodney A. Grann, Kerry Missler, Stephen R. Patterson, Jennifer Hu, Chun Gellenbeck, Kevin W. Scholten, Jeffrey D. Randolph, R. Keith
Abstract	Background Diacylglyceride acyltransferase 1 (DGAT1) is the enzyme that adds the final fatty acid on to a diacylglyceride during triglyceride (TG) synthesis. DGAT1 plays a key role in the repackaging of dietary TG into circulating TG rich chylomicrons. A growing amount of research has indicated that an exaggerated postprandial circulating TG level is a risk indicator for cardiovascular and metabolic disorders. The aim of this research was to identify a botanical extract that inhibits intestinal DGAT1 activity and attenuates postprandial hypertriglyceridemia in overweight and obese humans. Methods Twenty individual phytochemicals and an internal proprietary botanical extract library were screened with a primary cell-free DGAT1 enzyme assay that contained dioleoyl glycerol and palmitoleoyl Coenzyme A as substrates plus human intestinal microsomes as the DGAT1 enzyme source. Botanical extracts with IC50 values < 100 μg/mL were evaluated in a cellular DGAT1 assay. The cellular DGAT1 assay comprised the analysis of 14C labeled TG synthesis in cells incubated with 14C-glycerol and 0.3 mM oleic acid. Lead botanical extracts were then evaluated in a parallel, double-blind, placebo-controlled clinical trial. Ninety healthy, overweight and obese participants were randomized to receive 2 g daily of placebo or individual botanical extracts (the investigational product) for seven days. Serum TG levels were measured before and after consuming a high fat meal (HFM) challenge (0.354 L drink/shake; 77 g fat, 25 g carbohydrate and 9 g protein) as a marker of intestinal DGAT1 enzyme activity. Results Phenolic acids (i.e., gallic acid) and polyphenols (i.e., cyanidin) abundantly found in nature appeared to inhibit DGAT1 enzyme activity in vitro. Four polyphenolic rich botanical extracts were identified from in vitro evaluation in both cell-free and cellular model systems: apple peel extract (APE), grape extract (GE), red raspberry leaf extract (RLE) and apricot/nectarine extract (ANE) (IC50 = 1.4, 5.6, and 10.4 and 3.4 μg/mL, respectively). In the seven day clinical trial, compared to placebo, only GE significantly reduced the baseline subtracted change in serum TG AUC following consumption of the HFM (AUC = 281 ± 37 vs. 181 ± 30 mg/dL*h, respectively; P = 0.021). Chromatographic characterization of the GE revealed a large number of closely eluting components containing proanthocyanidins, catechins, anthocyanins and their secondary metabolites that corresponded with the observed DGAT1 enzyme inhibition in the cell-free model. Conclusion These data suggest that a dietary GE has the potential to attenuate postprandial hypertriglyceridemia in part by the inhibition of intestinal DGAT1 enzyme activity without intolerable side effects. Trial registration This trial was registered with ClinicalTrials.gov NCT02333461
Related Links	https://nutritionandmetabolism.biomedcentral.com/counter/pdf/10.1186/s12986-015-0025-2.pdf
Ending Page	13
Page Count	13
Starting Page	1
File Format	HTM / HTML
ISSN	17437075
DOI	10.1186/s12986-015-0025-2
Journal	Nutrition & Metabolism
Issue Number	1
Volume Number	12
Language	English
Publisher	BioMed Central
Publisher Date	2015-08-06
Access Restriction	Open
Subject Keyword	Clinical Nutrition Metabolic Diseases Icariin Investigational Product DGAT1 Activity Grape Extract Botanical Extract
Content Type	Text
Resource Type	Article
Subject	Medicine Endocrinology, Diabetes and Metabolism Nutrition and Dietetics
Journal Impact Factor	3.9/2023
5-Year Journal Impact Factor	4.3/2023

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