O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice
Abstract
:1. Introduction
2. Results
2.1. O-1602 Induces Lipid Accumulation through GPR55 in Hep3B Cells
2.2. O-1602 Induces Intracellular Ca2+ Increase in a GPR55-Independent Manner in Hep3B Cells
2.3. PI3K/Akt Signaling in the O-1602-Induced Lipid Accumulation in Hep3B Cells
2.4. O-1602 Induces SREBP-1c through GPR55 and PI3K in Hep3B Cells
2.5. Increase of Lysophosphatidylinosiltol Levels in Livers from High-Fat Diet-Fed Mice In Vivo
2.6. Administration of CID16020046 Reduced High-Fat Diet-Induced Lipid Accumulation in the Liver and O-1602-Induced Increase of Triglycerides Levels in the Serum
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Cell Culture and Treatment
4.3. Oil Red O Staining
4.4. Measurement of [Ca2+]i Concentrations
4.5. MTT Cytotoxicity Assay
4.6. Reverse Transcription-PCR
4.7. Western Blot
4.8. Measurement of Triglycerides
4.9. High Fat Diet Feeding
4.10. Lysophosphatidylinositol Extraction and LC-MS/MS Analysis
4.11. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
- Postic, C.; Girard, J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008, 34, 643–648. [Google Scholar] [CrossRef]
- Labonté, E.D.; Pfluger, P.T.; Cash, J.G.; Kuhel, D.G.; Roja, J.C.; Magness, D.P.; Jandacek, R.J.; Tschöp, M.H.; Hui, D.Y. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: The molecular link between group 1B phospholipase A2 and diet-induced obesity. FASEB J. 2010, 24, 2516–2524. [Google Scholar] [CrossRef] [Green Version]
- Helsley, R.N.; Varadharajan, V.; Brown, A.L.; Gromovsky, A.D.; Schugar, R.C.; Ramachandiran, I.; Fung, K.; Kabbany, M.N.; Banerjee, R.; Neumann, C.K.; et al. Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease. eLife 2019, 8, 49882. [Google Scholar] [CrossRef]
- Moreno-Navarrete, J.M.; Catalán, V.; Whyte, L.; Díaz-Arteaga, A.; Vázquez-Martínez, R.; Rotellar, F.; Guzmán, R.; Gómez-Ambrosi, J.; Pulido, M.R.; Russell, W.R. The L-α-lysophosphatidylinositol/GPR55 system and its potential role in human obesity. Diabetes 2012, 61, 281–291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oka, S.; Nakajima, K.; Yamashita, A.; Kishimoto, S.; Sugiura, T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem. Biophys. Res. Commun. 2007, 362, 928–934. [Google Scholar] [CrossRef] [PubMed]
- Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 2007, 152, 1092–1101. [Google Scholar] [CrossRef] [PubMed]
- Romero-Zerbo, S.Y.; Rafacho, A.; Díaz-Arteaga, A.; Suárez, J.; Quesada, I.; Imbernon, M.; Ross, R.A.; Dieguez, C.; De Fonseca, F.R.; Nogueiras, R.; et al. A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans. J. Endocrinol. 2011, 211, 177–185. [Google Scholar] [CrossRef] [Green Version]
- Kargl, J.; Brown, A.J.; Andersen, L.; Dorn, G.; Schicho, R.; Waldhoer, M.; Heinemann, A. A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function. J. Pharmacol. Exp. Ther. 2013, 346, 54–66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shimano, H.; Yahagi, N.; Amemiya-Kudo, M.; Hasty, A.H.; Osuga, J.-I.; Tamura, Y.; Shionoiri, F.; Iizuka, Y.; Ohashi, K.; Harada, K.; et al. Sterol Regulatory Element-binding Protein-1 as a Key Transcription Factor for Nutritional Induction of Lipogenic Enzyme Genes. J. Biol. Chem. 1999, 274, 35832–35839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yahagi, N.; Shimano, H.; Hasty, A.H.; Amemiya-Kudo, M.; Okazaki, H.; Tamura, Y.; Iizuka, Y.; Shionoiri, F.; Ohashi, K.; Osuga, J.-I.; et al. A Crucial Role of Sterol Regulatory Element-binding Protein-1 in the Regulation of Lipogenic Gene Expression by Polyunsaturated Fatty Acids. J. Biol. Chem. 1999, 274, 35840–35844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fondevila, M.F.; Fernandez, U.; Gonzalez-Rellan, M.J.; Da Silva Lima, N.; Buque, X.; Gonzalez-Rodriguez, A.; Alonso, C.; Iruarrizaga-Lejarreta, M.; Delgado, T.C.; Varela-Rey, M. The L-α-lysophosphatidylinositol/GPR55 system induces the development of non-alcoholic steatosis and steatohepatitis. Hepatology 2020, 73, 66. [Google Scholar]
- Magner, N.L.; Jung, Y.; Wu, J.; Nolta, J.A.; Zern, M.A.; Zhou, P. Insulin and igfs enhance hepatocyte differentiation from human embryonic stem cells via the PI3K/AKT pathway. Stem Cells 2013, 31, 2095–2103. [Google Scholar] [CrossRef] [Green Version]
- Molinaro, A.; Becattini, B.; Mazzoli, A.; Bleve, A.; Radici, L.; Maxvall, I.; Sopasakis, V.R.; Molinaro, A.; Bäckhed, F.; Solinas, G. Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. Cell Metab. 2019, 29, 1400–1409. [Google Scholar] [CrossRef]
- Henstridge, C.M.; Balenga, N.A.; Ford, L.A.; Ross, R.A.; Waldhoer, M.; Irving, A.J. The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J. 2009, 23, 183–193. [Google Scholar] [CrossRef] [PubMed]
- Liu, B.; Song, S.; Ruz-Maldonado, I.; Pingitore, A.; Huang, G.C.; Baker, D.; Jones, P.M.; Persaud, S.J. GPR55-dependent stimulation of insulin secretion from isolated mouse and human islets of Langerhans. Diabetes Obes. Metab. 2016, 18, 1263–1273. [Google Scholar] [CrossRef] [Green Version]
- Díaz-Arteaga, A.; Vázquez, M.J.; Vazquez-Martínez, R.; Pulido, M.R.; Suarez, J.; Velásquez, D.A.; López, M.; Ross, R.A.; De Fonseca, F.R.; Bermudez-Silva, F.J.; et al. The atypical cannabinoid O-1602 stimulates food intake and adiposity in rats. Diabetes, Obes. Metab. 2011, 14, 234–243. [Google Scholar] [CrossRef] [PubMed]
- Park, S.-J.; Lee, K.-P.; Kang, S.; Lee, J.; Sato, K.; Chung, H.Y.; Okajima, F.; Im, D.-S. Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4. Cell. Signal. 2014, 26, 2249–2258. [Google Scholar] [CrossRef] [PubMed]
- Park, S.-J.; Lee, K.-P.; Im, D.-S. Action and Signaling of Lysophosphatidylethanolamine in MDA-MB-231 Breast Cancer Cells. Biomol. Ther. 2014, 22, 129–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, K.-P.; Kang, S.; Park, S.-J.; Choi, Y.-W.; Lee, Y.-G.; Im, D.-S. Anti-allergic and anti-inflammatory effects of bakkenolide B isolated from Petasites japonicus leaves. J. Ethnopharmacol. 2013, 148, 890–894. [Google Scholar] [CrossRef] [PubMed]
- Kang, S.; Lee, K.-P.; Park, S.-J.; Noh, D.-Y.; Kim, J.-M.; Moon, H.R.; Lee, Y.-G.; Choi, Y.-W.; Im, D.-S. Identification of a novel anti-inflammatory compound, α-cubebenoate from Schisandra chinensis. J. Ethnopharmacol. 2014, 153, 242–249. [Google Scholar] [CrossRef]
- Matyash, V.; Liebisch, G.; Kurzchalia, T.V.; Shevchenko, A.; Schwudke, D. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J. Lipid Res. 2008, 49, 1137–1146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
No. | Compound | Adduct | Precursor Ion (m/z) | Product Ion (m/z) |
---|---|---|---|---|
1 | LPI 16:1 | [M+H+] | 585.3 | 311.3 |
2 | LPI 16:0 | 587.3 | 313.3 | |
3 | LPI 18:3 | 609.3 | 335.3 | |
4 | LPI 18:2 | 611.3 | 337.3 | |
5 | LPI 18:1 | 613.3 | 339.3 | |
6 | LPI 18:0 | 615.3 | 341.3 | |
7 | LPI 20:5 | 633.3 | 359.3 | |
8 | LPI 20:4 | 635.3 | 361.3 | |
9 | LPI 20:3 | 637.3 | 363.3 | |
10 | LPI 20:2 | 639.3 | 365.3 | |
11 | LPI 20:1 | 641.3 | 367.3 | |
12 | LPI 20:0 | 643.3 | 369.3 | |
13 | LPI 22:6 | 659.3 | 385.3 | |
14 | LPI 17:1 (IS) | 599.3 | 325.3 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kang, S.; Lee, A.-Y.; Park, S.-Y.; Liu, K.-H.; Im, D.-S. O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice. Int. J. Mol. Sci. 2021, 22, 3091. https://doi.org/10.3390/ijms22063091
Kang S, Lee A-Y, Park S-Y, Liu K-H, Im D-S. O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice. International Journal of Molecular Sciences. 2021; 22(6):3091. https://doi.org/10.3390/ijms22063091
Chicago/Turabian StyleKang, Saeromi, Ae-Yeon Lee, So-Young Park, Kwang-Hyeon Liu, and Dong-Soon Im. 2021. "O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice" International Journal of Molecular Sciences 22, no. 6: 3091. https://doi.org/10.3390/ijms22063091
APA StyleKang, S., Lee, A. -Y., Park, S. -Y., Liu, K. -H., & Im, D. -S. (2021). O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice. International Journal of Molecular Sciences, 22(6), 3091. https://doi.org/10.3390/ijms22063091