Ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells via bile acid receptor activation

Kim, Kyong; Park, Min; Lee, Yu Mi; Rhyu, Mee-Ra; Kim, Hye Young

doi:10.1007/s12272-014-0362-0

Cited by 48 publications

(42 citation statements)

References 20 publications

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“…To determine the potency of OL3 in stimulating GLP-1 secretion in vitro, NCI-H716 cells (a human enteroendocrine L cell line) endogenously expressing TGR5 [7,31,32] were employed. …”

Section: Ol3 Dose-dependently Stimulated Glp-1 Secretion In Nci-h716 mentioning

confidence: 99%

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

Ning

Zou

et al. 2016

Acta Pharmacol Sin

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Aim: TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. Methods: TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. Results: OL3 activated human and mouse TGR5 with an EC 50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3-30 μmol/L). OL3 inhibited human and mouse DPP-4 with IC 50 values of 18.44 and 69.98 μmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. Conclusion: OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects.

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“…To determine the potency of OL3 in stimulating GLP-1 secretion in vitro, NCI-H716 cells (a human enteroendocrine L cell line) endogenously expressing TGR5 [7,31,32] were employed. …”

Section: Ol3 Dose-dependently Stimulated Glp-1 Secretion In Nci-h716 mentioning

confidence: 99%

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

Ning

Zou

et al. 2016

Acta Pharmacol Sin

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“…Interestingly, actions of betulinic acid were markedly reduced once TGR5 receptor was silenced by siRNA in NCI-H716 cells. To produce the stable silencing, the siRNA used for TGR5 receptor included three targets: TAS1R3 and α-gustducin in addition to TGR5 receptor 12. However, it has been demonstrated that neither siRNA targeting TAS1R3 nor siRNA targeting α-gustducin in NCI-H716 cells influenced the GLP-1 secretion that was induced by a TGR5 receptor agonist 12.…”

Section: Discussionmentioning

confidence: 99%

“…As described in a previous report,12 CHO-K1 cells were transiently transfected with human G-protein-coupled BA receptor 1 and an expression vector (pCMV6-Entry; OriGene, Rockville, MD, USA). We used the TurboFect transfection reagent (Thermo Fisher Scientific, Pittsburgh, PA, USA) to transfect the cells, which were seeded at 5×10 4 cells per well in six-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Based on a previous method,12 we purchased a validated small interference RNA (siRNA) targeted against TGR5 from a commercial source (Dharmacon RNA Technology, Lafayette, CO, USA). The validated siRNAs were as follows: ON-TARGETplus SMARTpool siTAS1R3 (human NM_152228 sequence), ON-TARGETplus SMARTpool siGNAT3 (human NM_001102386 sequence), and ON-TARGETplus SMARTpool siGPBAR1 (TGR5) (human NM_170699 sequence).…”

Section: Methodsmentioning

confidence: 99%

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Development of betulinic acid as an agonist of TGR5 receptor using a new in vitro assay

Lo¹,

Cheng²,

Li³

et al. 2016

DDDT

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BackgroundG-protein-coupled bile acid receptor 1, also known as TGR5 is known to be involved in glucose homeostasis. In animal models, treatment with a TGR5 agonist induces incretin secretion to reduce hyperglycemia. Betulinic acid, a triterpenoid present in the leaves of white birch, has been introduced as a selective TGR5 agonist. However, direct activation of TGR5 by betulinic acid has not yet been reported.MethodsTransfection of TGR5 into cultured Chinese hamster ovary (CHO-K1) cells was performed to establish the presence of TGR5. Additionally, TGR5-specific small interfering RNA was employed to silence TGR5 in cells (NCI-H716 cells) that secreted incretins. Uptake of glucose by CHO-K1 cells was evaluated using a fluorescent indicator. Amounts of cyclic adenosine monophosphate and glucagon-like peptide were quantified using enzyme-linked immunosorbent assay kits.ResultsBetulinic acid dose-dependently increases glucose uptake by CHO-K1 cells transfected with TGR5 only, which can be considered an alternative method instead of radioligand binding assay. Additionally, signals coupled to TGR5 activation are also increased by betulinic acid in cells transfected with TGR5. In NCI-H716 cells, which endogenously express TGR5, betulinic acid induces glucagon-like peptide secretion via increasing calcium levels. However, the actions of betulinic acid were markedly reduced in NCI-H716 cells that received TGR5-silencing treatment. Therefore, the present study demonstrates the activation of TGR5 by betulinic acid for the first time.ConclusionSimilar to the positive control lithocholic acid, which is the established agonist of TGR5, betulinic acid has been characterized as a useful agonist of TGR5 and can be used to activate TGR5 in the future.

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“…13 Culture and endocrine differentiation of NCI-H716 cells (the American Type Culture Collection [ATCC], Manassas, VA, USA) were performed using previously published methods.…”

Section: Cell Culture and Viability Assaymentioning

confidence: 99%

Spergularia marina Induces Glucagon-Like Peptide-1 Secretion in NCI-H716 Cells Through Bile Acid Receptor Activation

Kim

Lee

Rhyu

et al. 2014

Journal of Medicinal Food

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Spergularia marina Griseb. (SM) is a halophyte that grows in mud flats. The aerial portions of SM have been eaten as vegetables and traditionally used to prevent chronic diseases in Korea. However, there has been no scientific report that demonstrates the pharmacological effects of SM. Glucagon-like peptide-1 (GLP-1) is important for the maintenance of glucose and energy homeostasis through acting as a signal in peripheral and neural systems. To discover a functional food for regulating glucose and energy homeostasis, we evaluated the effect of an aqueous ethanolic extract (AEE) of SM on GLP-1 release from enteroendocrine NCI-H716 cells. In addition, we explored the Takeda G-protein-coupled receptor 5 (TGR5) agonist activity of AEE-SM in Chinese hamster ovary (CHO)-K1 cells transiently transfected with human TGR5. As a result, treatment of NCI-H716 cells with AEE-SM increased GLP-1 secretion and intracellular Ca 2 + and cyclic AMP (cAMP) levels in a dose-dependent manner. Transfection of NCI-H716 cells with TGR5-specific small interference RNA inhibited AEE-SMinduced GLP-1 secretion and the increase in Ca 2 + and cAMP levels. Moreover, AEE-SM showed that the TGR5 agonist activity in CHO-K1 cells transiently transfected with TGR5. The results suggest that AEE-SM might be a candidate for a functional food to regulate glucose and energy homeostasis.

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Ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells via bile acid receptor activation

Cited by 48 publications

References 20 publications

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

Development of betulinic acid as an agonist of TGR5 receptor using a new in vitro assay

Spergularia marina Induces Glucagon-Like Peptide-1 Secretion in NCI-H716 Cells Through Bile Acid Receptor Activation

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