Betulinic acid lowers lipid accumulation in adipocytes through enhanced NCoA1–PPARγ interaction

Al-Mutary, Mohsen Ghaleb; Abu-Taweel, Gasem Mohammad; Rajagopal, Rajakrishnan; Kim, Sun-Ju; Kim, Hak-Jae; Kim, Young Ock; Mothana, Ramzi A.; Kadaikunnan, Shine; Khaled, Jamal M.; Siddiqui, Nasir A.; Al‐Rehaily, Adnan J.

doi:10.1016/j.jiph.2019.05.011

Cited by 18 publications

(19 citation statements)

References 25 publications

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“…The thyroid hormone receptor activator THRA gene is integrated and linked to obesity [84][85][86]. The NCOA1 gene in adipocytes has also been shown to be associated with metabolic disease [87][88][89]. The KSR2 gene [60,90,91] and FGF21 [92][93][94] are also integrated genes in the network associated with obesity, Figure 7 and S3.…”

Section: Discussionmentioning

confidence: 97%

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

et al. 2019

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The incidence of obesity has increased dramatically over the past two decades with a prevalence of approximately 40% of the adult population within the United States. The current study examines the potential for transgenerational adipocyte (fat cell) epigenetic alterations. Adipocytes were isolated from the gonadal fat pad of the great-grand offspring F3 generation 1-year old rats ancestrally exposed to DDT (dichlorodiphenyltrichloroethane), atrazine, or vehicle control in order to obtain adipocytes for DNA methylation analysis. Observations indicate that there were differential DNA methylated regions (DMRs) in the adipocytes with the lean or obese phenotypes compared to control normal (non-obese or lean) populations. The comparison of epigenetic alterations indicated that there were substantial overlaps between the different treatment lineage groups for both the lean and obese phenotypes. Novel correlated genes and gene pathways associated with DNA methylation were identified, and may aid in the discovery of potential therapeutic targets for metabolic diseases such as obesity. Observations indicate that ancestral exposures during critical windows of development can induce the epigenetic transgenerational inheritance of DNA methylation changes in adipocytes that ultimately may contribute to an altered metabolic phenotype. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 97%

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

et al. 2019

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“…28 Similarly, betulinic acid at concentrations up to 10 μM has been shown to have no adverse effects on HepG2 cells, whereas the IC 50 value for these cells has been established to be 160 μM. 29 Given these disparate observations, the concentrations of betulinic acid that are nontoxic to HepG2 cells have yet to be conclusively determined. Accordingly, in the present study, we sought to determine the optimal treatment concentration of betulinic acid using the MTT assay (Figure 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Betulinic Acid Suppresses de novo Lipogenesis by Inhibiting Insulin and IGF1 Signaling as Upstream Effectors of the Nutrient-Sensing mTOR Pathway

Kim

Park

Shin

et al. 2021

J. Agric. Food Chem.

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Despite its beneficial properties, effects of betulinic acid on the nutrient-sensing mTOR pathway via insulin or IGF1 signaling remain unclear. Here, we investigated whether betulinic acid reduces intracellular lipid accumulation via the nutrientsensing pathway in HepG2 cells. Results showed that betulinic acid reduced intracellular lipid accumulation in a dose-dependent manner and inhibited the expression of de novo lipogenesis-related genes and proteins. RNA sequencing analysis revealed the transcriptional modulation of plasma membrane proteins by betulinic acid, and an in silico binding assay indicated an interaction between betulinic acid and IR or IGF1R. Furthermore, betulinic acid downregulated the post-translational modification of the canonical IRS1/PI3K/AKT-pT308 and IGF1/mTORC2/AKT-pS473 pathways, thereby reducing the activity of the mTOR/S6K/ S6 pathway. These findings imply that betulinic acid suppresses hepatic lipid synthesis by inhibiting insulin and IGF1 signaling as upstream effectors of the nutrient-sensing mTOR pathway and could be a potent nutraceutical agent for the treatment of metabolic syndromes.

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“…BA has been extensively studied for its anti-cancer and anti-viral activities (Moghaddam, Ahmad & Samzadeh-Kermani, 2012). Recent studies showed its potential roles in balancing immunity and metabolisms including bone and lipid metabolisms (Birgani et al, 2018;Mohsen et al, 2019;Ríos & Máñez, 2018). It has been shown that BA reduced adipogenesis in mouse preadipocytes with decreases in C/EBP-a, PPARγ, GLUT4, cation diffusion facilitator, and perilipin one expressions (Brusotti et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Betulinic acid decreases lipid accumulation in adipogenesis-induced human mesenchymal stem cells with upregulation of PGC-1α and UCP-1 and post-transcriptional downregulation of adiponectin and leptin secretion

Senamontree

Lakthan

Charoenpanich

et al. 2021

PeerJ

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Background Controlling cellular functions, including stem cell growth and differentiation, can be the key for the treatment of metabolic disorders, such as type II diabetes mellitus (T2DM). Previously identified as peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, betulinic acid (BA) may have the capability to control stem cell homeostasis, benefiting T2DM treatment. In this study, the effects of BA on osteogenesis and adipogenesis mechanisms of human mesenchymal stem cells (hMSCs) were investigated. Results We observed that BA increased hMSC osteogenesis by enhancing the alkaline phosphatase activity, calcium deposition, and mRNA expressions of osteogenic markers, namely, runt-related transcription factor 2, osteocalcin, and osteopontin. In addition, BA decreased hMSC adipogenesis with the decrease in glycerol-3-phosphate dehydrogenase activity, reduced intracellular lipid accumulations, down-regulated CCAAT-enhancer-binding protein alpha, and suppressed post-transcriptional adiponectin and leptin secretion. BA increased the brown adipocyte characteristics with the increase in the ratio of small lipid droplets and glucose uptake. Furthermore, the mRNA expressions of brown adipocyte markers, namely, PPARγ coactivator one alpha, uncoupling protein 1, and interleukin-6 increased. Conclusions Our results uncovered the mechanisms of how BA improved glucose and lipid metabolisms by decreasing white adipogenesis and increasing brown adipogenesis. Altogether, BA may be used for balancing glucose metabolisms without the potential side effects on bone loss or weight gain.

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Betulinic acid lowers lipid accumulation in adipocytes through enhanced NCoA1–PPARγ interaction

Cited by 18 publications

References 25 publications

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

Betulinic Acid Suppresses de novo Lipogenesis by Inhibiting Insulin and IGF1 Signaling as Upstream Effectors of the Nutrient-Sensing mTOR Pathway

Betulinic acid decreases lipid accumulation in adipogenesis-induced human mesenchymal stem cells with upregulation of PGC-1α and UCP-1 and post-transcriptional downregulation of adiponectin and leptin secretion

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