Robinetin Alleviates Metabolic Failure in Liver Through Suppression of P300-CD38 Axis

Overview

Journal Biomol Ther (Seoul)

Specialty Pharmacology

Date 2024 Feb 1

PMID 38298012

Authors

Ji-Hye Song

Hyo-Jin Kim

Jangho Lee

Seung-Pyo Hong

Min-Yu Chung

Yu-Geun Lee

Jae Ho Park

Hyo-Kyoung Choi

Jin-Taek Hwang

Affiliations

Soon will be listed here.

Abstract

Metabolic abnormalities in the liver are closely associated with diverse metabolic diseases such as non-alcoholic fatty liver disease, type 2 diabetes, and obesity. The aim of this study was to evaluate the ameliorating effect of robinetin (RBN) on the significant pathogenic features of metabolic failure in the liver and to identify the underlying molecular mechanism. RBN significantly decreased triglyceride (TG) accumulation by downregulating lipogenesis-related transcription factors in AML-12 murine hepatocyte cell line. In addition, mice fed with Western diet (WD) containing 0.025% or 0.05% RBN showed reduced liver mass and lipid droplet size, as well as improved plasma insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. CD38 was identified as a target of RBN using the BioAssay database, and its expression was increased in OPA-treated AML-12 cells and liver tissues of WD-fed mice. Furthermore, RBN elicited these effects through its anti-histone acetyltransferase (HAT) activity. Computational simulation revealed that RBN can dock into the HAT domain pocket of p300, a histone acetyltransferase, which leads to the abrogation of its catalytic activity. Additionally, knock-down of using siRNA reduced CD38 expression. The chromatin immunoprecipitation (ChIP) assay showed that p300 occupancy on the promoter region of CD38 was significantly decreased, and H3K9 acetylation levels were diminished in lipid-accumulated AML-12 cells treated with RBN. RBN improves the pathogenic features of metabolic failure by suppressing the p300-CD38 axis through its anti-HAT activity, which suggests that RBN can be used as a new phytoceutical candidate for preventing or improving this condition.

References

Sarwar R, Pierce N, Koppe S . Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes Metab Syndr Obes. 2018; 11:533-542. PMC: 6163009. DOI: 10.2147/DMSO.S146339. View

Barbosa M, Soares S, Novak C, Sinclair D, Levine J, Aksoy P . The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 2007; 21(13):3629-39. DOI: 10.1096/fj.07-8290com. View

Tolsma T, Hansen J . Post-translational modifications and chromatin dynamics. Essays Biochem. 2019; 63(1):89-96. DOI: 10.1042/EBC20180067. View

Hennig A, Peng G, Chen S . Transcription coactivators p300 and CBP are necessary for photoreceptor-specific chromatin organization and gene expression. PLoS One. 2013; 8(7):e69721. PMC: 3724885. DOI: 10.1371/journal.pone.0069721. View

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

Morandi F, Horenstein A, Costa F, Giuliani N, Pistoia V, Malavasi F . CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. Front Immunol. 2018; 9:2722. PMC: 6279879. DOI: 10.3389/fimmu.2018.02722. View

Chung M, Song J, Lee J, Shin E, Park J, Lee S . Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. Mol Metab. 2018; 19:34-48. PMC: 6323241. DOI: 10.1016/j.molmet.2018.11.001. View

Bowers E, Yan G, Mukherjee C, Orry A, Wang L, Holbert M . Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol. 2010; 17(5):471-82. PMC: 2884008. DOI: 10.1016/j.chembiol.2010.03.006. View

Chiang S, Harrington W, Luo G, Milliken N, Ulrich J, Chen J . Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility. PLoS One. 2015; 10(8):e0134927. PMC: 4546114. DOI: 10.1371/journal.pone.0134927. View

10.

Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T . Regulation of cellular metabolism by protein lysine acetylation. Science. 2010; 327(5968):1000-4. PMC: 3232675. DOI: 10.1126/science.1179689. View

11.

Kim S, Cho B, Kim U . CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: attenuation of hepatic fibrosis by CD38 ablation. J Biol Chem. 2009; 285(1):576-82. PMC: 2804206. DOI: 10.1074/jbc.M109.076216. View

12.

Thompson P, Wang D, Wang L, Fulco M, Pediconi N, Zhang D . Regulation of the p300 HAT domain via a novel activation loop. Nat Struct Mol Biol. 2004; 11(4):308-15. DOI: 10.1038/nsmb740. View

13.

Camacho-Pereira J, Tarrago M, Chini C, Nin V, Escande C, Warner G . CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016; 23(6):1127-1139. PMC: 4911708. DOI: 10.1016/j.cmet.2016.05.006. View

14.

Wang L, Miao L, Wang X, Huang C, Qian Y, Huang X . CD38 deficiency suppresses adipogenesis and lipogenesis in adipose tissues through activating Sirt1/PPARγ signaling pathway. J Cell Mol Med. 2017; 22(1):101-110. PMC: 5742727. DOI: 10.1111/jcmm.13297. View

15.

Escande C, Nin V, Price N, Capellini V, Gomes A, Barbosa M . Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes. 2012; 62(4):1084-93. PMC: 3609577. DOI: 10.2337/db12-1139. View

16.

Kessoku T, Imajo K, Honda Y, Kato T, Ogawa Y, Tomeno W . Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep. 2016; 6:22251. PMC: 4766502. DOI: 10.1038/srep22251. View

17.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S . PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2018; 47(D1):D1102-D1109. PMC: 6324075. DOI: 10.1093/nar/gky1033. View

18.

Verdone L, Agricola E, Caserta M, Di Mauro E . Histone acetylation in gene regulation. Brief Funct Genomic Proteomic. 2006; 5(3):209-21. DOI: 10.1093/bfgp/ell028. View

19.

Eslam M, Valenti L, Romeo S . Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol. 2017; 68(2):268-279. DOI: 10.1016/j.jhep.2017.09.003. View

20.

Piedra-Quintero Z, Wilson Z, Nava P, Guerau-de-Arellano M . CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity. Front Immunol. 2020; 11:597959. PMC: 7734206. DOI: 10.3389/fimmu.2020.597959. View