Betulinic Acid has an Inhibitory Effect on Pancreatic Lipase and Induces Adipocyte Lipolysis

Kim, Jung-Hyun; Lee, Young Seub; Kim, Chan-Sik; Kim, Jin Sook

doi:10.1002/ptr.3672

Cited by 53 publications

(34 citation statements)

References 9 publications

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“…In this study, we also observed a reduction in fat mass of white adipocytes in BA‐treated obese mice. A similar weight loss was also observed in other BA studies (Kim et al, ). Intriguingly, BA treatment elevated the core rectal temperature and the gene expressions of Cidea and Glut4 in BAT in DIO mice, suggesting an enhanced energy expenditure.…”

Section: Discussionsupporting

confidence: 89%

“…Several studies have reported that BA exerts therapeutic effects on obesity and type 2 diabetes (Kim et al, ; Kim, Lee, Kim, & Kim, ); however, few studies have focused on NAFLD, and the underlying molecular mechanism of BA is obscure. We found that BA activated FXR transcriptional activity in a ligand‐driven coactivator manner but had no effect on the other nuclear hormone receptors analysed.…”

Section: Discussionmentioning

confidence: 99%

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Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Ping

Zhang

et al. 2019

British J Pharmacology

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Background and Purpose: The molecular mechanism for the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains elusive. Both farnesoid X receptor (FXR) signalling and endoplasmic reticulum (ER) stress contribute to the progression of NAFLD; however, it is not clear whether the actions of these two pathways are dependent on each other. Moreover, the pharmacological benefits and mechanism of betulinic acid (BA) in controlling metabolic syndrome and NAFLD are largely unknown.Experimental Approach: A reporter assay and a time-resolved FRET assay were used to identify BA as an agonist of the FXR. NAFLD was induced by a methionine and choline-deficient L-amino acid diet (MCD) and high-fat diet (HFD). The pharmacological effects of BA (100 mg·kg −1 ·day −1 ) and potential interactions between hepatic FXR activation and ER stress pathways were evaluated by FXR silencing, Western blot and RT-PCR analyses using control and FXR −/− mice.Key Results: Activation of the FXR inhibited intracellular PERK/EIF2α/ATF4 and CHOP signalling, thereby alleviating hepatic ER stress, whereas FXR silencing resulted in an opposite effect. Furthermore, we identified BA as an FXR agonist that effectively attenuated the progression of NAFLD and metabolic disorders in both HFD-and MCD diet-fed mice and restored the hepatocellular ER homeostasis by stimulating the FXR signalling pathway and blocking PERK/EIF2α signalling. In contrast, the effects of BA were attenuated in FXR −/− mice. Conclusions and Implications:Our data demonstrate that pharmacological activation of the FXR by BA reduces hepatocellular ER stress and attenuates NAFLD in an animal model of hepatic steatosis.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Ping

Zhang

et al. 2019

British J Pharmacology

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“…The overall antidiabetic effect of A. roxburghiana could be attributed to multiple effects including the present finding of PTP1B inhibition, insulin secretagogue activity 10 and other effects reported for the active ingredients, betulin and betulinic acid [25][26][27] . Experimental data obtained from our computational insights study further revealed that the C-3 hydroxyl and C-17 carboxylic acid positions of the pentacyclic triterpene skeleton are critical for designing new and better PTP1B inhibitors.…”

Section: Resultssupporting

confidence: 58%

“…Since, some of the compounds identified in the present study were known to occur in A. roxburghiana 25 , our study appears to be the first report on the identification of active compounds against PTP1B principles of the plant. The antidiabetic effect of betulinic acid could also be mediated through other effects including inhibition of pancreatic lipase and adipocyte lipolysis 26 and also by enhancing glucose uptake in adipocytes after long treatment 27 . The PTP1B inhibitory effect of betulin has not been reported before but it is known to improve hyperlipidemia and insulin resistance in experimental animals 28 .…”

Section: Resultsmentioning

confidence: 99%

Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

Shah

Ishtiaq

Hizbullah

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Artemisia roxburghiana is used in traditional medicine for treating various diseases including diabetes. The present study was designed to evaluate the antidiabetic potential of active constituents by using protein tyrosine phosphatase 1B (PTP1B) as a validated target for management of diabetes. Various compounds were isolated as active principles from the crude methanolic extract of aerial parts of A. roxburghiana. All compounds were screened for PTP1B inhibitory activity. Molecular docking simulations were performed to investigate the mechanism behind PTP1B inhibition of the isolated compound and positive control, ursolic acid. Betulinic acid, betulin and taraxeryl acetate were the active PTP1B principles with IC 50 values 3.49 ± 0.02, 4.17 ± 0.03 and 87.52 ± 0.03 mM, respectively. Molecular docking studies showed significant molecular interactions of the triterpene inhibitors with Gly220, Cys215, Gly218 and Asp48 inside the active site of PTP1B. The antidiabetic activity of A. roxburghiana could be attributed due to PTP1B inhibition by its triterpene constituents, betulin, betulinic acid and taraxeryl acetate. Computational insights of this study revealed that the C-3 and C-17 positions of the compounds needs extensive optimization for the development of new lead compounds.

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“…Some of them down-regulated lipid accumulation and insulin induced 3T3-L1 differentiation, reduced adipocyte size, while others decreased the levels of all adipogenic proteins and glucose transporter type 4 (GLUT4), but increased adiponectin (Nishina et al, 2017). Betulinic acid has been reported to have a strong lipolytic effect mediated by cAMP-dependent phosphodiesterase inhibition (Kim et al, 2012). Cucrumin has a certain beneficial effect on regulating glucose and lipid metabolism.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Causes and solutions to “globesity”: The new fa(s)t alarming global epidemic

Vasileva

Marchev

Georgiev

2018

Food and Chemical Toxicology

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Diverse groups of factors are leading to increased weight gain and obesity, such as certain genetic phenotypes, neuroendocrine disturbances, the administration of some drugs, behavioral, social and environmental factors. The progressively escalating rates of overweight and obesity worldwide have led to an introduction of a new term "globesity". Excessive accumulation of body fat and especially of visceral adipose tissue is the main predisposing factor for the development of metabolic syndrome and other obesity related co-morbidities. At the present moment only few pharmacotherapeuticals are used for long-term treatment of obesity acting on narrow target spectra, e.g. pancreatic and gastric lipase inhibition, acting as adrenomimetics or activating the satiety centers in hypothalamus. Plant-based medications that accelerate weight loss, proved to be safe, effective and widely available, would be a preferable alternative for anti-obesity treatments. As plant extracts are multi-component systems they could also act by more than one mechanism, including decreased lipid absorption, decreased energy intake, increased energy expenditure, decreased pre-adipocyte differentiation and proliferation, decreased lipogenesis and increased lipolysis. The current review gives a summary of the risk factors for obesity development and its characteristics consequences. Current treatment options, combining lifestyle changes and conventional treatment with commercial anti-obesity drugs have been described as well. Special emphasis on in vitro, in vivo and human studies, of potential medicinal plant extracts and phytochemicals, such as polyphenols, terpenoids, alkaloids, saponins, able to modulate the molecular pathways and gene/protein expressions related to obesity, have been highlighted.

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Betulinic Acid has an Inhibitory Effect on Pancreatic Lipase and Induces Adipocyte Lipolysis

Cited by 53 publications

References 9 publications

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice

Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

Causes and solutions to “globesity”: The new fa(s)t alarming global epidemic

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