Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model
Publication: Canadian Journal of Physiology and Pharmacology
22 June 2023
Abstract
The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRβ, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRβ-specific agonist. We aimed to examine whether OBG specifically affects LXRβ in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (−) group, and (IV) OBG (+) group. All groups’ rats were intraperitoneally administered L-NAME. The L-NAME/OBG group’s rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) group’s rats were administered OBG, while the OBG (−) group’s rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRβ-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.
Graphical Abstract
Get full access to this article
View all available purchase options and get full access to this article.
References
Ahn S.B., Jang K., Jun D.W., Lee B.H., Shin K.J. 2014. Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease. Dig. Dis. Sci. 59: 2975–2982.
Blaustein M.P., Zhang J., Chen L., Song H., Raina H., Kinsey S.P., et al. 2009. The pump, the exchanger, and endogenous ouabain: signaling mechanisms that link salt retention to hypertension. Hypertension, 53: 291–298.
Calkin A.C., Tontonoz P. 2010. Liver X receptor signaling pathways and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30: 1513–1518.
Cave M.C., Clair H.B., Hardesty J.E., Falkner K.C., Feng W., Clark B.J., et al. 2016. Nuclear receptors and nonalcoholic fatty liver disease. Biochim. Biophys. Acta. 1859: 1083–1099.
Collins J.L., Fivush A.M., Watson M.A., Galardi C.M., Lewis M.C., Moore L.B., et al. 2002. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J. Med. Chem. 45: 1963–1966.
Drobny M., Pullmann R., Odalos I., Skerenova M., Saniova B. 2014. Incidence of skeletal muscle disorders after statins' treatment: consequences in clinical and EMG picture. Neuro Endocrinol. Lett. 35: 123–128.
Ekstedt M., Hagström H., Nasr P., Fredrikson M., Stål P., Kechagias S., Hultcrantz R. 2015. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology, 61: 1547–1554.
Elias J. Jr., Altun E., Zacks S., Armao D.M., Woosley J.T., Semelka R.C. 2009. MRI findings in nonalcoholic steatohepatitis: correlation with histopathology and clinical staging. Magn. Reson. Imaging, 27: 976–987.
Gebe J.A., Kiener P.A., Ring H.Z., Li X., Francke U., Aruffo A. 1997. Molecular cloning, mapping to human chromosome 1 q21-q23, and cell binding characteristics of Spalpha, a new member of the scavenger receptor cysteine-rich (SRCR) family of proteins. J. Biol. Chem. 272: 6151–6158.
Ghisletti S., Huang W., Ogawa S., Pascual G., Lin M.E., Willson T.M., et al. 2007. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ. Mol. Cell, 25: 57–70.
Goodman Z.D. 2007. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J. Hepatol. 47: 598–607.
Guthrie D., Gibson A.L. 1977. Doxorubicin cardiotoxicity: possible role of digoxin in its prevention. Br. Med. J. 2: 1447–1449.
Hong C., Tontonoz P. 2014. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat. Rev. Drug Discov. 13: 433–444.
Ishak K., Baptista A., Bianchi L., Callea F., de Groote J., Gudat F., et al. 1995. Histological grading and staging of chronic hepatitis. J. Hepatol. 22: 696–699.
Katz A., Udata C., Ott E., Hickey L., Burczynski M.E., Burghart P., et al. 2009. Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X-receptor agonist, in healthy participants. J. Clin. Pharmacol. 49: 643–649.
Kennedy M.A., Barrera G.C., Nakamura K., Baldán A., Tarr P., Fishbein M.C., et al. 2005. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 1: 121–131.
Kitamori K., Naito H., Tamada H., Kobayashi M., Miyazawa D., Yasui Y., et al. 2012. Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr. Environ. Health Prev. Med. 17: 173–182.
Kleiner D.E., Brunt E.M., Van Natta M., Behling C., Contos M.J., Cummings O.W., et al. 2005. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 41: 1313–1321.
Kumar R., Yankopoulos N.A., Abelmann W.H. 1973. Ouabain-induced hypertension in a patient with decompensated hypertensive heart disease. Chest, 63: 105–108.
Kumazaki S., Nakamura M., Sasaki S., Tagashira R., Maruyama N., Sato I., et al. 2019. Bile acid metabolism is an intermediary factor between non-alcoholic steatohepatitis and ischemic heart disease in SHRSP5/Dmcr rats. J. Nutr. Food Sci. 09.
Kunimasa K., Yoshitomi H., Miura C., Mori H., Tsuchikura S., Ikeda K., et al. 2010. High susceptibility of obese hypertensive SHRSP.Z-Lepr (fa)/IzmDmcr rats to lipid deposition in the mesenteric artery. Clin. Exp. Pharmacol. Physiol. 37: 1102–1104.
Li X., Yeh V., Molteni V. 2010. Liver X receptor modulators: a review of recently patented compounds (2007–2009). Expert Opin. Ther. Pat. 20: 535–562.
Ma Z., Deng C., Hu W., Zhou J., Fan C., Di S., et al. 2017. Liver X receptors and their agonists: targeting for cholesterol homeostasis and cardiovascular diseases. Curr. Issues Mol. Biol. 22: 41–64.
Miyazaki T., Hirokami Y., Matsuhashi N., Takatsuka H., Naito M. 1999. Increased susceptibility of thymocytes to apoptosis in mice lacking AIM, a novel murine macrophage-derived soluble factor belonging to the scavenger receptor cysteine-rich domain superfamily. J. Exp. Med. 189: 413–422.
Nd A.M. 2019. Non-alcoholic fatty liver disease, an overview. Integr. Med. (Encinitas), 18: 42–49.
Oni E.T., Agatston A.S., Blaha M.J., Fialkow J., Cury R., Sposito A., et al. 2013. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis, 230: 258–267.
Oram J.F., Heinecke J.W. 2005. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol. Rev. 85: 1343–1372.
Repa J.J., Liang G., Ou J., Bashmakov Y., Lobaccaro J.M., Shimomura I., et al. 2000. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 14: 2819–2830.
Rinella M.E. 2015. Nonalcoholic fatty liver disease: a systematic review. JAMA, 313: 2263–2273.
Rosenson R.S., Brewer H.B. Jr., Davidson W.S., Fayad Z.A., Fuster V., Goldstein J., et al. 2012. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation, 125: 1905–1919.
Rossier B.C. 2014. Epithelial sodium channel (ENaC) and the control of blood pressure. Curr. Opin. Pharmacol. 15: 33–46.
Russo M.W., Hoofnagle J.H., Gu J., Fontana R.J., Barnhart H., Kleiner D.E., et al. 2014. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology, 60: 679–686.
Sarig S., Utian W.H., Sheean L.A., Gorodeski G.I. 1995. Distribution of unesterified cholesterol-containing particles in human atherosclerotic lesions. Am. J. Pathol. 146: 139–147.
Schultz J.R., Tu H., Luk A., Repa J.J., Medina J.C., Li L., et al. 2000. Role of LXRs in control of lipogenesis. Genes Dev. 14: 2831–2838.
Sookoian S., Pirola C.J. 2008. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J. Hepatol. 49: 600–607.
Tamura S., Okada M., Kato S., Shinoda Y., Shioda N., Fukunaga K., et al. 2018. Ouabagenin is a naturally occurring LXR ligand without causing hepatic steatosis as a side effect. Sci. Rep. 8: 2305.
Targher G., Bertolini L., Poli F., Rodella S., Scala L., Tessari R., et al. 2005. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes, 54: 3541–3546.
Targher G., Day C.P., Bonora E. 2010. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363: 1341–1350.
Targher G., Byrne C.D., Lonardo A., Zoppini G., Barbui C. 2016. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J. Hepatol. 65: 589–600.
Tymiak A.A., Norman J.A., Bolgar M., Didonato G.C., Lee H., Parker W.L., et al. 1993. Physicochemical characterization of a ouabain isomer isolated from bovine hypothalamus. Proc. Natl. Acad. Sci. U.S.A. 90: 8189–8193.
Valledor A.F., Hsu L.C., Ogawa S., Sawka-Verhelle D., Karin M., Glass C.K. 2004. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc. Natl. Acad. Sci. U.S.A. 101: 17813–17818.
Warnock D.G., Kusche-Vihrog K., Tarjus A., Sheng S., Oberleithner H., Kleyman T.R., Jaisser F. 2014. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells. Nat. Rev. Nephrol. 10: 146–157.
Watanabe S., Kumazaki S., Kusunoki K., Inoue T., Maeda Y., Usui S., et al. 2018a. A high-fat and high-cholesterol diet induces cardiac fibrosis, vascular endothelial, and left ventricular diastolic dysfunction in SHRSP5/Dmcr rats. J. Atheroscler. Thromb. 25: 439–453.
Watanabe S., Kumazaki S., Yamamoto S., Sato I., Kitamori K., Mori M., et al. 2018b. Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model. Int. J. Exp. Pathol. 99: 282–294.
Yamamoto S., Sato I., Fukuhama N., Akiyama N., Sakai M., Kumazaki S., et al. 2020. Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model. Exp. Mol. Pathol. 114: 104437.
Zhang Y., Pan Y., Lin C., Zheng Y., Sun H., Zhang H., et al. 2016. Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy. J. Mol. Cell. Biol. 8: 530–541.
Information & Authors
Information
Published In
Canadian Journal of Physiology and Pharmacology
Volume 101 • Number 9 • September 2023
Pages: 455 - 465
History
Received: 16 November 2022
Accepted: 26 April 2023
Accepted manuscript online: 24 May 2023
Version of record online: 22 June 2023
Copyright
© 2023 The Author(s). Permission for reuse (free in most cases) can be obtained from copyright.com.
Data Availability Statement
Data are not available.
Key Words
Authors
Author Contributions
Conceptualization: SY, SW
Data curation: SY, IS, MF, MK, KH, SK, HN, TF, SW
Formal analysis: SY
Funding acquisition: SW
Investigation: SY, IS, MF, MK, KH, SK, HN, TF
Methodology: SW
Resources: ST, MU
Visualization: SY
Writing – original draft: SY
Writing – review & editing: SH, SW
Competing Interests
The authors declare that there are no competing interests.
Funding Information
This work was supported by the Japan Society for the Promotion of Sciences (JSPS) Grants-in-Aid for Scientific Research (Grant numbers 18K10993, 20H00548, and 23K16796).
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoru Tamura, Minoru Ueda, Satoshi Hirohata, and Shogo Watanabe. 2023. Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model. Canadian Journal of Physiology and Pharmacology.
101(9): 455-465. https://doi.org/10.1139/cjpp-2022-0532
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
Login options
Check if you access through your login credentials or your institution to get full access on this article.
Subscribe
Click on the button below to subscribe to Canadian Journal of Physiology and Pharmacology