Knockdown of RASD1 Improves MASLD Progression by Inhibiting the PI3K/AKT/mTOR Pathway

Overview

Journal Lipids Health Dis

Publisher Biomed Central

Specialties Biochemistry
Endocrinology

Date 2024 Dec 28

PMID 39731125

Authors

Guifang Zeng

Xialei Liu

Zhouying Zheng

Jiali Zhao

Wenfeng Zhuo

Zirui Bai

En Lin

Shanglin Cai

Chaonong Cai

Peiping Li

Baojia Zou

Jian Li

Affiliations

Soon will be listed here.

Abstract

Background: There is still no reliable therapeutic targets and effective pharmacotherapy for metabolic dysfunction-associated steatotic liver disease (MASLD). RASD1 is short for Ras-related dexamethasone-induced 1, a pivotal factor in various metabolism processes of Human. However, the role of RASD1 remains poorly illustrated in MASLD. Therefore, we designed a study to elucidate how RASD1 could impact on MASLD as well as the mechanisms involved.

Methods: The expression level of RASD1 was validated in MASLD. Lipid metabolism and its underlying mechanism were investigated in hepatocytes and mice with either overexpression or knockdown of RASD1.

Results: Hepatic RASD1 expression was upregulated in MASLD. Lipid deposition was significantly reduced in RASD1-knockdown hepatocytes and mice, accompanied by a marked downregulation of key genes in the signaling pathway of de novo lipogenesis. Conversely, RASD1 overexpression in hepatocytes had the opposite effect. Mechanistically, RASD1 regulated lipid metabolism in MASLD through the PI3K/AKT/mTOR signaling pathway.

Conclusions: We discovered a novel role of RASD1 in MASLD by regulating lipogenesis via the PI3K/AKT/mTOR pathway, thereby identifying a potential treatment target for MASLD.

References

Shimano H, Yahagi N, Amemiya-Kudo M, Hasty A, Osuga J, Tamura Y . Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem. 1999; 274(50):35832-9. DOI: 10.1074/jbc.274.50.35832. View

Kumar S, Agnihotri N . Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer. Biomed Pharmacother. 2018; 109:1462-1477. DOI: 10.1016/j.biopha.2018.10.182. View

Younossi Z, Anstee Q, Marietti M, Hardy T, Henry L, Eslam M . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2017; 15(1):11-20. DOI: 10.1038/nrgastro.2017.109. View

Miao L, Targher G, Byrne C, Cao Y, Zheng M . Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab. 2024; 35(8):697-707. DOI: 10.1016/j.tem.2024.02.007. View

Ter Horst K, Serlie M . Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease. Nutrients. 2017; 9(9). PMC: 5622741. DOI: 10.3390/nu9090981. View

Smith G, Shankaran M, Yoshino M, Schweitzer G, Chondronikola M, Beals J . Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2019; 130(3):1453-1460. PMC: 7269561. DOI: 10.1172/JCI134165. View

Virtue S, Vidal-Puig A . GTTs and ITTs in mice: simple tests, complex answers. Nat Metab. 2021; 3(7):883-886. DOI: 10.1038/s42255-021-00414-7. View

Shimano H, Sato R . SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol. 2017; 13(12):710-730. DOI: 10.1038/nrendo.2017.91. View

Porstmann T, Santos C, Griffiths B, Cully M, Wu M, Leevers S . SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008; 8(3):224-36. PMC: 2593919. DOI: 10.1016/j.cmet.2008.07.007. View

10.

Song Q, Rao Y, Tang G, Sun Z, Zhang J, Huang Z . Tigliane Diterpenoids as a New Type of Antiadipogenic Agents Inhibit GRα-Dexras1 Axis in Adipocytes. J Med Chem. 2019; 62(4):2060-2075. DOI: 10.1021/acs.jmedchem.8b01693. View

11.

Rinella M, Lazarus J, Ratziu V, Francque S, Sanyal A, Kanwal F . A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023; 79(6):1542-1556. DOI: 10.1016/j.jhep.2023.06.003. View

12.

Cornu M, Albert V, Hall M . mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev. 2013; 23(1):53-62. DOI: 10.1016/j.gde.2012.12.005. View

13.

Bass J, Takahashi J . Circadian integration of metabolism and energetics. Science. 2010; 330(6009):1349-54. PMC: 3756146. DOI: 10.1126/science.1195027. View

14.

Tong J, Cong L, Jia Y, He B, Guo Y, He J . Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway. Diabetes Metab Syndr Obes. 2022; 15:3285-3301. PMC: 9621035. DOI: 10.2147/DMSO.S380053. View

15.

Palaschak B, Herzog R, Markusic D . AAV-Mediated Gene Delivery to the Liver: Overview of Current Technologies and Methods. Methods Mol Biol. 2019; 1950:333-360. DOI: 10.1007/978-1-4939-9139-6_20. View

16.

Sun C, Zhang J, Hou J, Hui M, Qi H, Lei T . Induction of autophagy via the PI3K/Akt/mTOR signaling pathway by Pueraria flavonoids improves non-alcoholic fatty liver disease in obese mice. Biomed Pharmacother. 2022; 157:114005. DOI: 10.1016/j.biopha.2022.114005. View

17.

Cheng H, Obrietan K . Dexras1: shaping the responsiveness of the circadian clock. Semin Cell Dev Biol. 2006; 17(3):345-51. DOI: 10.1016/j.semcdb.2006.03.006. View

18.

Bertot L, Adams L . The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016; 17(5). PMC: 4881593. DOI: 10.3390/ijms17050774. View

19.

Dou C, Sun L, Wang L, Cheng J, Wu W, Zhang C . Bromodomain-containing protein 9 promotes the growth and metastasis of human hepatocellular carcinoma by activating the TUFT1/AKT pathway. Cell Death Dis. 2020; 11(9):730. PMC: 7481201. DOI: 10.1038/s41419-020-02943-7. View

20.

Tu Y, Wu C . Cloning, expression and characterization of a novel human Ras-related protein that is regulated by glucocorticoid hormone. Biochim Biophys Acta. 2000; 1489(2-3):452-6. DOI: 10.1016/s0167-4781(99)00197-9. View