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The Natural Products Journal

Editor-in-Chief

ISSN (Print): 2210-3155
ISSN (Online): 2210-3163

Research Article

Cannabidiol and Indole-3-carbinol Reduce Intracellular Lipid Droplet Accumulation in HepaRG, A Human Liver Cell Line, as well as in Human Adipocytes

Author(s): Sanjanaa Senthilkumar, Megan E. Solan, Maria T. Fernandez-Luna and Ramon Lavado*

Volume 14, Issue 2, 2024

Published on: 18 July, 2023

Article ID: e260523217374 Pages: 10

DOI: 10.2174/2210315513666230526100544

Price: $65

Abstract

Introduction: An increase in obesity-related diseases is becoming an alarming worldwide problem. Therefore, new therapeutic methods are constantly sought to prevent, treat, and alleviate symptoms of the diseases associated with obesity.

Method: This study investigates the effects of two natural compounds (indole-3-carbinol, I3C, a bioactive indolic compound found in cruciferous vegetables; cannabidiol, CBD, the active ingredient derived from the hemp plant) on the fatty acid accumulation in the human liver cell line HepaRG, a well-established model for non-alcoholic fatty liver disease (NAFLD) and in human pre-adipocytes (adipose-derived mesenchymal stem cells, MSC).

Results: EC50s of each compound were in the high μM range (approximately 30 mg/L), showing the low toxicity of these compounds. Determination of the selected compounds in cell media showed no significant differences during the exposure, suggesting that no significant metabolism or degradation happened during the exposure time. Quantification of the bioaccumulation of lipid droplets on exposed HepaRG revealed a significant reduction and mitigation of fatty acid accumulation when exposed to 1 nM of I3C and 100 nM of CBD.). On MSC cells a significant inhibition of lipogenesis and adipocyte differentiation was observed in cells exposed to 0.1 nM of I3C and 1 nM of CBD.

Conclusion: This study provides a significant contribution to advancing the understanding of preventative dietary strategies that target adipocyte differentiation and NAFLD.

Keywords: Lipogenesis, indole-3carbinol, cannabidiol, HepaRG, adipocytes, natural products.

Graphical Abstract
[1]
Tremmel, M.; Gerdtham, U.G.; Nilsson, P.; Saha, S. Economic burden of obesity: A systematic literature review. Int. J. Environ. Res. Public Health, 2017, 14(4), 435.
[http://dx.doi.org/10.3390/ijerph14040435] [PMID: 28422077]
[2]
Younossi, Z.M. Non-alcoholic fatty liver disease-a global public health perspective. J. Hepatol., 2019, 70(3), 531-544.
[http://dx.doi.org/10.1016/j.jhep.2018.10.033] [PMID: 30414863]
[3]
Al-Dayyat, H.M.; Rayyan, Y.M.; Tayyem, R.F. Non-alcoholic fatty liver disease and associated dietary and lifestyle risk factors. Diabetes Metab. Syndr., 2018, 12(4), 569-575.
[http://dx.doi.org/10.1016/j.dsx.2018.03.016] [PMID: 29571977]
[4]
Neuschwander-Tetri, B.A. Non-alcoholic fatty liver disease. BMC Med., 2017, 15(1), 45.
[http://dx.doi.org/10.1186/s12916-017-0806-8] [PMID: 28241825]
[5]
Natesan, V.; Kim, S.J. Lipid metabolism, disorders and therapeutic drugs-review. Biomol. Ther., 2021, 29(6), 596-604.
[http://dx.doi.org/10.4062/biomolther.2021.122] [PMID: 34697272]
[6]
Liu, X.; Tong, W.; Zhao, X.; Zhang, H.; Tang, Y.; Deng, X. Chinese herb extract improves liver steatosis by promoting the expression of high molecular weight adiponectin in NAFLD rats. Mol. Med. Rep., 2017, 16(4), 5580-5586.
[http://dx.doi.org/10.3892/mmr.2017.7284] [PMID: 28849192]
[7]
Xiao, J.; So, K.F.; Liong, E.C.; Tipoe, G.L. Recent advances in the herbal treatment of non-alcoholic Fatty liver disease. J. Tradit. Complement. Med., 2013, 3(2), 88-94.
[http://dx.doi.org/10.4103/2225-4110.110411] [PMID: 24716162]
[8]
Yao, H.; Qiao, Y.J.; Zhao, Y.L.; Tao, X.F.; Xu, L.N.; Yin, L.H.; Qi, Y.; Peng, J.Y. Herbal medicines and nonalcoholic fatty liver disease. World J. Gastroenterol., 2016, 22(30), 6890-6905.
[http://dx.doi.org/10.3748/wjg.v22.i30.6890] [PMID: 27570425]
[9]
Dong, H.; Lu, F.; Zhao, L. Chinese herbal medicine in the treatment of nonalcoholic fatty liver disease. Chin. J. Integr. Med., 2012, 18(2), 152-160.
[http://dx.doi.org/10.1007/s11655-012-0993-2] [PMID: 22311412]
[10]
Liu, L.; Yang, M.; Lin, X.; Li, Y.; Liu, C.; Yang, Y.; Yamahara, J.; Wang, J.; Li, Y. Modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to Salacia oblonga root-elicited improvement of fructose-induced fatty liver in rats. J. Ethnopharmacol., 2013, 150(3), 1045-1052.
[http://dx.doi.org/10.1016/j.jep.2013.10.020] [PMID: 24157375]
[11]
Lee, M.J.; Fried, S.K. Optimal protocol for the differentiation and metabolic analysis of human adipose stromal cells. Methods Enzymol., 2014, 538, 49-65.
[http://dx.doi.org/10.1016/B978-0-12-800280-3.00004-9] [PMID: 24529433]
[12]
Foulds, C.E.; Treviño, L.S.; York, B.; Walker, C.L. Endocrine-disrupting chemicals and fatty liver disease. Nat. Rev. Endocrinol., 2017, 13(8), 445-457.
[http://dx.doi.org/10.1038/nrendo.2017.42] [PMID: 28524171]
[13]
Li, X.; Pham, H.T.; Janesick, A.S.; Blumberg, B. Triflumizole is an obesogen in mice that acts through peroxisome proliferator activated receptor gamma (PPARγ). Environ. Health Perspect., 2012, 120(12), 1720-1726.
[http://dx.doi.org/10.1289/ehp.1205383] [PMID: 23086663]
[14]
Zuo, Z.; Chen, S.; Wu, T.; Zhang, J.; Su, Y.; Chen, Y.; Wang, C. Tributyltin causes obesity and hepatic steatosis in male mice. Environ. Toxicol., 2011, 26(1), 79-85.
[http://dx.doi.org/10.1002/tox.20531] [PMID: 19760618]
[15]
Green, H.; Kehinde, O. Sublines of mouse 3T3 cells that accumulate lipid. Cell, 1974, 1(3), 113-116.
[http://dx.doi.org/10.1016/0092-8674(74)90126-3]
[16]
Scott, M.A.; Nguyen, V.T.; Levi, B.; James, A.W. Current methods of adipogenic differentiation of mesenchymal stem cells. Stem Cells Dev., 2011, 20(10), 1793-1804.
[http://dx.doi.org/10.1089/scd.2011.0040] [PMID: 21526925]
[17]
Berger, E.; Héraud, S.; Mojallal, A.; Lequeux, C.; Weiss-Gayet, M.; Damour, O.; Géloën, A. Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis. Adipocyte, 2015, 4(3), 161-180.
[http://dx.doi.org/10.4161/21623945.2014.987578] [PMID: 26257990]
[18]
Fenwick, G.R.; Heaney, R.K.; Mullin, W.J.; VanEtten, C.H. Glucosinolates and their breakdown products in food and food plants. CRC Crit. Rev. Food Sci. Nutr., 1983, 18(2), 123-201.
[http://dx.doi.org/10.1080/10408398209527361] [PMID: 6337782]
[19]
Chang, H.P.; Wang, M.L.; Chan, M.H.; Chiu, Y.S.; Chen, Y.H. Antiobesity activities of indole-3-carbinol in high-fat-diet–induced obese mice. Nutrition, 2011, 27(4), 463-470.
[http://dx.doi.org/10.1016/j.nut.2010.09.006] [PMID: 21392705]
[20]
Choi, Y.; Kim, Y.; Park, S.; Lee, K.W.; Park, T. Indole-3-carbinol prevents diet-induced obesity through modulation of multiple genes related to adipogenesis, thermogenesis or inflammation in the visceral adipose tissue of mice. J. Nutr. Biochem., 2012, 23(12), 1732-1739.
[http://dx.doi.org/10.1016/j.jnutbio.2011.12.005] [PMID: 22569347]
[21]
Choi, Y.; Um, S-J.; Park, T. Indole-3-carbinol directly targets SIRT1 to inhibit adipocyte differentiation. Int. J. Obes., 2013, 37(6), 881-884.
[http://dx.doi.org/10.1038/ijo.2012.158] [PMID: 22986685]
[22]
Hegde, V.L.; Singh, U.P.; Nagarkatti, P.S.; Nagarkatti, M. Critical role of mast cells and peroxisome proliferator-activated receptor γ in the induction of myeloid-derived suppressor cells by marijuana cannabidiol in vivo. J. Immunol., 2015, 194(11), 5211-5222.
[http://dx.doi.org/10.4049/jimmunol.1401844] [PMID: 25917103]
[23]
Stienstra, R.; Duval, C.; Müller, M.; Kersten, S. PPARs, obesity, and inflammation. PPAR Res., 2007, 2007, 1-10.
[http://dx.doi.org/10.1155/2007/95974] [PMID: 17389767]
[24]
Blaschke, F.; Takata, Y.; Caglayan, E.; Law, R.E.; Hsueh, W.A. Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 2006, 26(1), 28-40.
[http://dx.doi.org/10.1161/01.ATV.0000191663.12164.77] [PMID: 16239592]
[25]
Vettor, R.; Pagano, C. The role of the endocannabinoid system in lipogenesis and fatty acid metabolism. Best Pract. Res. Clin. Endocrinol. Metab., 2009, 23(1), 51-63.
[http://dx.doi.org/10.1016/j.beem.2008.10.002] [PMID: 19285260]
[26]
Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol., 2015, 172(20), 4790-4805.
[http://dx.doi.org/10.1111/bph.13250] [PMID: 26218440]
[27]
Cerec, V.; Glaise, D.; Garnier, D.; Morosan, S.; Turlin, B.; Drenou, B.; Gripon, P.; Kremsdorf, D.; Guguen-Guillouzo, C.; Corlu, A. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor. Hepatology, 2007, 45(4), 957-967.
[http://dx.doi.org/10.1002/hep.21536] [PMID: 17393521]
[28]
Smith, M.C.; Gheux, A.; Coton, M.; Madec, S.; Hymery, N.; Coton, E. In vitro co-culture models to evaluate acute cytotoxicity of individual and combined mycotoxin exposures on Caco-2, THP-1 and HepaRG human cell lines. Chem. Biol. Interact., 2018, 281, 51-59.
[http://dx.doi.org/10.1016/j.cbi.2017.12.004] [PMID: 29222052]
[29]
Guillouzo, A.; Corlu, A.; Aninat, C.; Glaise, D.; Morel, F.; Guguen-Guillouzo, C. The human hepatoma HepaRG cells: A highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem. Biol. Interact., 2007, 168(1), 66-73.
[http://dx.doi.org/10.1016/j.cbi.2006.12.003] [PMID: 17241619]
[30]
Aninat, C.; Piton, A.; Glaise, D.; Le Charpentier, T.; Langouët, S.; Morel, F.; Guguen-Guillouzo, C.; Guillouzo, A. Expression of cytochromes P450, Conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab. Dispos., 2006, 34(1), 75-83.
[http://dx.doi.org/10.1124/dmd.105.006759] [PMID: 16204462]
[31]
Brook, C.G.D.; Lloyd, J.K.; Wolf, O.H. Relation between age of onset of obesity and size and number of adipose cells. BMJ, 1972, 2(5804), 25-27.
[http://dx.doi.org/10.1136/bmj.2.5804.25] [PMID: 5015967]
[32]
Rubin, C.T.; Capilla, E.; Luu, Y.K.; Busa, B.; Crawford, H.; Nolan, D.J.; Mittal, V.; Rosen, C.J.; Pessin, J.E.; Judex, S. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc. Natl. Acad. Sci. USA, 2007, 104(45), 17879-17884.
[http://dx.doi.org/10.1073/pnas.0708467104] [PMID: 17959771]
[33]
Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411), 143-147.
[http://dx.doi.org/10.1126/science.284.5411.143] [PMID: 10102814]
[34]
Ullah, I.; Subbarao, R.B.; Rho, G.J. Human mesenchymal stem cells-current trends and future prospective. Biosci. Rep., 2015, 35(2), e00191.
[http://dx.doi.org/10.1042/BSR20150025] [PMID: 25797907]
[35]
Tascher, G.; Burban, A.; Camus, S.; Plumel, M.; Chanon, S.; Le Guevel, R.; Shevchenko, V.; Van Dorsselaer, A.; Lefai, E.; Guguen-Guillouzo, C.; Bertile, F. In-depth proteome analysis highlights HepaRG cells as a versatile cell system surrogate for primary human hepatocytes. Cells, 2019, 8(2), 192.
[http://dx.doi.org/10.3390/cells8020192] [PMID: 30795634]
[36]
Millar, S.A.; Stone, N.L.; Yates, A.S.; O’Sullivan, S.E. A systematic review on the pharmacokinetics of cannabidiol in humans. Front. Pharmacol., 2018, 9.
[http://dx.doi.org/10.3389/fphar.2018.01365]
[37]
Anderton, M.J.; Manson, M.M.; Verschoyle, R.D.; Gescher, A.; Lamb, J.H.; Farmer, P.B.; Steward, W.P.; Williams, M.L. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin. Cancer Res., 2004, 10(15), 5233-5241.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0163] [PMID: 15297427]
[38]
Ricchi, M.; Odoardi, M.R.; Carulli, L.; Anzivino, C.; Ballestri, S.; Pinetti, A.; Fantoni, L.I.; Marra, F.; Bertolotti, M.; Banni, S.; Lonardo, A.; Carulli, N.; Loria, P. Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J. Gastroenterol. Hepatol., 2009, 24(5), 830-840.
[http://dx.doi.org/10.1111/j.1440-1746.2008.05733.x] [PMID: 19207680]
[39]
Zgair, A.; Wong, J.C.M.; Sabri, A.; Fischer, P.M.; Barrett, D.A.; Constantinescu, C.S.; Gershkovich, P. Development of a simple and sensitive HPLC–UV method for the simultaneous determination of cannabidiol and Δ9-tetrahydrocannabinol in rat plasma. J. Pharm. Biomed. Anal., 2015, 114, 145-151.
[http://dx.doi.org/10.1016/j.jpba.2015.05.019] [PMID: 26048666]
[40]
Li, Z.; Wei, X.; Li, L.; Liu, Y.; Fang, Z.; Yang, L.; Zhuang, M.; Zhang, Y.; Lv, H. Development of a simple method for determination of anti-cancer component of indole-3-carbinol in cabbage and broccoli. J. Food Nutr. Res. (Newark), 2017, 5(9), 642-648.
[http://dx.doi.org/10.12691/jfnr-5-9-3]
[41]
Franco, M.E.; Fernandez-Luna, M.T.; Ramirez, A.J.; Lavado, R. Metabolomic-based assessment reveals dysregulation of lipid profiles in human liver cells exposed to environmental obesogens. Toxicol. Appl. Pharmacol., 2020, 398, 115009.
[http://dx.doi.org/10.1016/j.taap.2020.115009] [PMID: 32353385]
[42]
Lillie, R.; Ashburn, L. Supersaturated solutions of fat stains in dilute isopropanol for demonstration of acute fatty degeneration not shown by Herxheimer’s technique. Arch. Pathol., 1943, 36, 432-440.
[43]
Ramírez-Zacarías, J.L.; Castro-Muñozledo, F.; Kuri-Harcuch, W. Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry, 1992, 97(6), 493-497.
[http://dx.doi.org/10.1007/BF00316069] [PMID: 1385366]
[44]
Qiu, B.; Simon, M. BODIPY 493/503 staining of neutral lipid droplets for microscopy and quantification by flow cytometry. Bio Protoc., 2016, 6(17), e1912.
[http://dx.doi.org/10.21769/BioProtoc.1912] [PMID: 28573161]
[45]
Walther, T.C.; Farese, R.V., Jr Lipid droplets and cellular lipid metabolism. Annu. Rev. Biochem., 2012, 81(1), 687-714.
[http://dx.doi.org/10.1146/annurev-biochem-061009-102430] [PMID: 22524315]
[46]
Franco, M.E.; Sutherland, G.E.; Fernandez-Luna, M.T.; Lavado, R. Altered expression and activity of phase I and II biotransformation enzymes in human liver cells by perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS). Toxicology, 2020, 430, 152339.
[http://dx.doi.org/10.1016/j.tox.2019.152339] [PMID: 31809754]
[47]
Stohs, S.J.; Ray, S.D. Is cannabidiol hepatotoxic or hepatoprotective: A review. Toxicol. Res. Appl., 2020, 4
[http://dx.doi.org/10.1177/2397847320922944]
[48]
Ewing, L.E.; Skinner, C.M.; Quick, C.M.; Kennon-McGill, S.; McGill, M.R.; Walker, L.A.; ElSohly, M.A.; Gurley, B.J.; Koturbash, I. Hepatotoxicity of a cannabidiol-rich cannabis extract in the mouse model. Molecules, 2019, 24(9), 1694.
[http://dx.doi.org/10.3390/molecules24091694] [PMID: 31052254]
[49]
Cerretani, D.; Collodel, G.; Brizzi, A.; Fiaschi, A.I.; Menchiari, A.; Moretti, E.; Moltoni, L.; Micheli, L. Cytotoxic effects of cannabinoids on human HT-29 colorectal adenocarcinoma cells: Different mechanisms of THC, CBD, and CB83. Int. J. Mol. Sci., 2020, 21(15), 5533.
[http://dx.doi.org/10.3390/ijms21155533] [PMID: 32752303]
[50]
Chen, L.; Cheng, P.H.; Rao, X.M.; McMasters, K.M.; Zhou, H.S. Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis. Cancer Biol. Ther., 2014, 15(9), 1256-1267.
[http://dx.doi.org/10.4161/cbt.29690] [PMID: 24972095]
[51]
a) B., Lam; and Z.M., Younossi Treatment options for nonalcoholic fatty liver disease. Therap. Adv. Gastroenterol., 2010, 3(2), 121-137.;
b) Drewnowski, A.; Eichelsdoerfer, P. Can low-income americans afford a healthy diet? Nutr. Today, 2009, 44(6), 246-249.
[http://dx.doi.org/10.1097/NT.0b013e3181c29f79] [PMID: 20368762]
[52]
Doumas, M.; Imprialos, K.; Dimakopoulou, A.; Stavropoulos, K.; Binas, A.; Athyros, V.G. The role of statins in the management of nonalcoholic fatty liver disease. Curr. Pharm. Des., 2019, 24(38), 4587-4592.
[http://dx.doi.org/10.2174/1381612825666190117114305] [PMID: 30652643]
[53]
Esposito, G.; Scuderi, C.; Valenza, M.; Togna, G.I.; Latina, V.; De Filippis, D.; Cipriano, M.; Carratù, M.R.; Iuvone, T.; Steardo, L. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One, 2011, 6(12), e28668.
[http://dx.doi.org/10.1371/journal.pone.0028668] [PMID: 22163051]
[54]
Friedenstein, A.J.; Petrakova, K.V.; Kurolesova, A.I.; Frolova, G.P. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 1968, 6(2), 230-247.
[http://dx.doi.org/10.1097/00007890-196803000-00009] [PMID: 5654088]
[55]
Meirelles, L.S.; Chagastelles, P.C.; Nardi, N.B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci., 2006, 119(11), 2204-2213.
[http://dx.doi.org/10.1242/jcs.02932] [PMID: 16684817]
[56]
Zuk, P.A.; Zhu, M.; Mizuno, H.; Huang, J.; Futrell, J.W.; Katz, A.J.; Benhaim, P.; Lorenz, H.P.; Hedrick, M.H. Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Eng., 2001, 7(2), 211-228.
[http://dx.doi.org/10.1089/107632701300062859] [PMID: 11304456]
[57]
Fink, T.; Zachar, V. Adipogenic differentiation of human mesenchymal stem cells. Methods Mol. Biol., 2011, 698, 243-251.
[http://dx.doi.org/10.1007/978-1-60761-999-4_19] [PMID: 21431524]
[58]
Ruiz de Azua, I.; Mancini, G.; Srivastava, R.K.; Rey, A.A.; Cardinal, P.; Tedesco, L.; Zingaretti, C.M.; Sassmann, A.; Quarta, C.; Schwitter, C.; Conrad, A.; Wettschureck, N.; Vemuri, V.K.; Makriyannis, A.; Hartwig, J.; Mendez-Lago, M.; Bindila, L.; Monory, K.; Giordano, A.; Cinti, S.; Marsicano, G.; Offermanns, S.; Nisoli, E.; Pagotto, U.; Cota, D.; Lutz, B. Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages. J. Clin. Invest., 2017, 127(11), 4148-4162.
[http://dx.doi.org/10.1172/JCI83626] [PMID: 29035280]
[59]
Katz, E.; Nisani, S.; Chamovitz, D.A. ndole-3-carbinol: A plant hormone combatting cancer. F1000 Res., 2018, 7, 1689.
[http://dx.doi.org/10.12688/f1000research.14127.1]
[60]
Fahey, J.W.; Zalcmann, A.T.; Talalay, P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry, 2001, 56(1), 5-51.
[http://dx.doi.org/10.1016/S0031-9422(00)00316-2] [PMID: 11198818]
[61]
Agerbirk, N.; De Vos, M.; Kim, J.H.; Jander, G. Indole glucosinolate breakdown and its biological effects. Phytochem. Rev., 2009, 8(1), 101-120.
[http://dx.doi.org/10.1007/s11101-008-9098-0]
[62]
Choi, Y.; Abdelmegeed, M.A.; Song, B.J. Preventive effects of indole-3-carbinol against alcohol-induced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms: Role of gut-liver-adipose tissue axis. J. Nutr. Biochem., 2018, 55, 12-25.
[http://dx.doi.org/10.1016/j.jnutbio.2017.11.011] [PMID: 29331880]
[63]
Ma, L.; Li, H.; Hu, J.; Zheng, J.; Zhou, J.; Botchlett, R.; Matthews, D.; Zeng, T.; Chen, L.; Xiao, X.; Athrey, G.; Threadgill, D.W.; Li, Q.; Glaser, S.; Francis, H.; Meng, F.; Li, Q.; Alpini, G.; Wu, C. Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3. Hepatology, 2020, 72(4), 1191-1203.
[http://dx.doi.org/10.1002/hep.31115] [PMID: 31953865]
[64]
Wang, M.L.; Lin, S.H.; Hou, Y.Y.; Chen, Y.H. Suppression of lipid accumulation by indole-3-carbinol is associated with increased expression of the aryl hydrocarbon receptor and CYP1B1 proteins in adipocytes and with decreased adipocyte-stimulated endothelial tube formation. Int. J. Mol. Sci., 2016, 17(8), 1256.
[http://dx.doi.org/10.3390/ijms17081256] [PMID: 27527145]
[65]
Chang, R.C.; Thangavelu, C.S.; Joloya, E.M.; Kuo, A.; Li, Z.; Blumberg, B. Cannabidiol promotes adipogenesis of human and mouse mesenchymal stem cells via PPARγ by inducing lipogenesis but not lipolysis. Biochem. Pharmacol., 2022, 197, 114910.
[http://dx.doi.org/10.1016/j.bcp.2022.114910] [PMID: 35026188]
[66]
Schwarz, J.M.; Neese, R.A.; Turner, S.; Dare, D.; Hellerstein, M.K. Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. J. Clin. Invest., 1995, 96(6), 2735-2743.
[http://dx.doi.org/10.1172/JCI118342] [PMID: 8675642]
[67]
Furuhashi, M.; Saitoh, S.; Shimamoto, K.; Miura, T. Fatty acid-binding protein 4 (FABP4): Pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. Clin. Med. Insights Cardiol., 2015, 8(Suppl. 3), 23-33.
[http://dx.doi.org/10.4137/CMC.S17067] [PMID: 25674026]
[68]
Keller, P.; Petrie, J.T.; De Rose, P.; Gerin, I.; Wright, W.S.; Chiang, S.H.; Nielsen, A.R.; Fischer, C.P.; Pedersen, B.K.; MacDougald, O.A. Fat-specific protein 27 regulates storage of triacylglycerol. J. Biol. Chem., 2008, 283(21), 14355-14365.
[http://dx.doi.org/10.1074/jbc.M708323200] [PMID: 18334488]
[69]
Garin-Shkolnik, T.; Rudich, A.; Hotamisligil, G.S.; Rubinstein, M. FABP4 attenuates PPARγ and adipogenesis and is inversely correlated with PPARγ in adipose tissues. Diabetes, 2014, 63(3), 900-911.
[http://dx.doi.org/10.2337/db13-0436] [PMID: 24319114]
[70]
Jung, T.; Hudson, R.; Rushlow, W.; Laviolette, S.R. Functional interactions between cannabinoids, omega-3 fatty acids, and peroxisome proliferator-activated receptors: Implications for mental health pharmacotherapies. Eur. J. Neurosci., 2022, 55(4), 1088-1100.
[http://dx.doi.org/10.1111/ejn.15023] [PMID: 33108021]
[71]
Sonego, A.B.; Prado, D.S.; Vale, G.T.; Sepulveda-Diaz, J.E.; Cunha, T.M.; Tirapelli, C.R.; Del Bel, E.A.; Raisman-Vozari, R.; Guimarães, F.S. Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors. Brain Behav. Immun., 2018, 74, 241-251.
[http://dx.doi.org/10.1016/j.bbi.2018.09.014] [PMID: 30217539]

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