Abstract
Pancreatic lipase (PL) inhibitor therapy has been validated as an efficacious way for preventing and treating obesity and overweight. In the past few decades, porcine PL (pPL) is widely used as the enzyme source for screening the PL inhibitors, which generates a wide range of pPL inhibitors. By contrast, the efficacious inhibitors against human PL (hPL) are rarely reported. This study aims to discover the naturally occurring hPL inhibitors from edible herbal medicines (HMs) and to characterize the inhibitory mechanisms of the newly identified hPL inhibitors. Following the screening of the inhibition potentials of more than 100 HMs against hPL, Ampelopsis grossedentata extract (AGE) displayed the most potent hPL inhibition activity. After that, the major constituents in AGE were identified and purified, while their anti-hPL effects were assayed in vitro. The results clearly showed that two abundant constituents in AGE (dihydromyricetin and iso-dihydromyricetin) were moderate hPL inhibitors, while myricetin and quercetin were strong hPL inhibitors [half-maximal inhibitory concentration (IC50) values were around 1.5 μM]. Inhibition kinetic analyses demonstrated that myricetin and quercetin potently inhibited hPL-catalyzed near-infrared fluorogenic substrate of human pancreatic lipase (DDAO-ol) hydrolysis in a non-competitive inhibition manner, with Ki values of 2.04 and 2.33 μM, respectively. Molecular dynamics simulations indicated that myricetin and quercetin could stably bind on an allosteric site of hPL. Collectively, this study reveals the key anti-obesity constituents in AGE and elucidates their inhibitory mechanisms against hPL, which offers convincing evidence to support the anti-obesity and lipid-lowering effects of this edible herb.
Highlights
Obesity and obesity-associated metabolic disorders are serious and global public health problems [1, 2]
These results demonstrate that Ampelopsis grossedentata extract (AGE) inhibits human PL (hPL)-catalyzed DDAO-ol hydrolysis via a dose-dependent and reversible manner, implying that this herbal medicines (HMs) contains naturally occurring hPL inhibitor(s)
This work reported the discovery of the bioactive anti-hPL substances from AGE, edible folk medicine in South China, and characterized the inhibitory mechanisms of the newly identified anti-hPL substances from this edible herb
Summary
Obesity and obesity-associated metabolic disorders are serious and global public health problems [1, 2]. The prevalence of obesity is strongly associated with a variety of metabolic disorders, such as hypertension, cardiovascular diseases, non-alcoholic liver disease, type II diabetes, stroke, and various types of cancer [11–13]. Reducing the morbidity related to obesity has become a public health priority. Over the past few decades, several feasible strategies have been proposed for preventing and treating obesity, such as blocking lipid absorption, accelerating lipid metabolism, regulating lipid accumulation, and lipid signal transduction, as well as gastrectomy [14]. Among all reported strategies for preventing and treating obesity, blocking lipid absorption by using food or herbal products to lose weight is very popular for obese patients [15, 16]
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