Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation

Fatema Al-Rashed; Hossein Arefanian; Ashraf Al Madhoun; Fatemah Bahman; Halemah AlSaeed; Texy Jacob; Reeby Thomas; Areej Al-Roub; Sardar Sindhu; Fawaz Alzaid; Md. Zubbair Malik; Rasheeba Nizam; Thangavel Alphonse Thanaraj; Fahd Al-Mulla; Yusuf A Hannun; Rasheed Ahmad

doi:10.20944/preprints202310.0273.v1

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preprints.org > biology and life sciences > endocrinology and metabolism > doi: 10.20944/preprints202310.0273.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation

^* ,

Thangavel Alphonse Thanaraj

Fahd Al-Mulla

Yusuf A Hannun

Rasheed Ahmad

Version 1 : Received: 5 October 2023 / Approved: 5 October 2023 / Online: 5 October 2023 (09:27:30 CEST)

How to cite: Al-Rashed, F.; Arefanian, H.; Madhoun, A.A.; Bahman, F.; AlSaeed, H.; Jacob, T.; Thomas, R.; Al-Roub, A.; Sindhu, S.; Alzaid, F.; Malik, M.Z.; Nizam, R.; Thanaraj, T.A.; Al-Mulla, F.; Hannun, Y.A.; Ahmad, R. Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation. Preprints 2023, 2023100273. https://doi.org/10.20944/preprints202310.0273.v1 Al-Rashed, F.; Arefanian, H.; Madhoun, A.A.; Bahman, F.; AlSaeed, H.; Jacob, T.; Thomas, R.; Al-Roub, A.; Sindhu, S.; Alzaid, F.; Malik, M.Z.; Nizam, R.; Thanaraj, T.A.; Al-Mulla, F.; Hannun, Y.A.; Ahmad, R. Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation. Preprints 2023, 2023100273. https://doi.org/10.20944/preprints202310.0273.v1

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MDPI and ACS Style

Al-Rashed, F.; Arefanian, H.; Madhoun, A.A.; Bahman, F.; AlSaeed, H.; Jacob, T.; Thomas, R.; Al-Roub, A.; Sindhu, S.; Alzaid, F.; Malik, M.Z.; Nizam, R.; Thanaraj, T.A.; Al-Mulla, F.; Hannun, Y.A.; Ahmad, R. Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation. Preprints 2023, 2023100273. https://doi.org/10.20944/preprints202310.0273.v1

APA Style

Al-Rashed, F., Arefanian, H., Madhoun, A.A., Bahman, F., AlSaeed, H., Jacob, T., Thomas, R., Al-Roub, A., Sindhu, S., Alzaid, F., Malik, M.Z., Nizam, R., Thanaraj, T.A., Al-Mulla, F., Hannun, Y.A., & Ahmad, R. (2023). Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation. Preprints. https://doi.org/10.20944/preprints202310.0273.v1

Chicago/Turabian Style

Al-Rashed, F., Yusuf A Hannun and Rasheed Ahmad. 2023 "Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steato-sis and Inflammation" Preprints. https://doi.org/10.20944/preprints202310.0273.v1

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here we report studies that address this question. Methods: 14 weeks on high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Results: Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and prevent cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Conclusions: Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.

Keywords

NAFLD; SMPD3; Lipotoxicity; HepG2; TNF-α; sphingomyelin pathway; RNA sequencing; Oil Red O staining; fat accumulation; Obesity

Subject

Biology and Life Sciences, Endocrinology and Metabolism

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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