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Eliminating senescent cells by white adipose tissue–targeted senotherapy alleviates age-related hepatic steatosis through decreasing lipolysis

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Abstract

Cellular senescence is an important risk factor in the development of hepatic steatosis. Senolytics present therapeutic effects on age-related hepatic steatosis without eliminating senescent hepatocytes directly. Therefore, it highlights the need to find senolytics’ therapeutic targets. Dysfunction of adipose tissue underlies the critical pathogenesis of lipotoxicity in the liver. However, the correlation between adipose tissue and hepatic steatosis during aging and its underlying molecular mechanism remains poorly understood. We explored the correlation between white adipose tissue (WAT) and the liver during aging and evaluated the effect of lipolysis of aged WAT on hepatic steatosis and hepatocyte senescence. We screened out the ideal senolytics for WAT and developed a WAT-targeted delivery system for senotherapy. We assessed senescence and lipolysis of WAT and hepatic lipid accumulation after treatment. The results displayed that aging accelerated cellular senescence and facilitated lipolysis of WAT. Free fatty acids (FFAs) generated by WAT during aging enhanced hepatic steatosis and induced hepatocyte senescence. The combined usage of dasatinib and quercetin was screened out as the ideal senolytics to eliminate senescent cells in WAT. To minimize non-specific distribution and enhance the effectiveness of senolytics, liposomes decorated with WAT affinity peptide P3 were constructed for senotherapy in vivo. In vivo study, WAT-targeted treatment eliminated senescent cells in WAT and reduced lipolysis, resulting in the alleviation of hepatic lipid accumulation and hepatocyte senescence when compared to non-targeted treatment, providing a novel tissue-targeted, effective and safe senotherapy for age-related hepatic steatosis.

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Abbreviations

WAT:

White adipose tissue

SCs:

Senescent cells

SASP:

Senescence-associated secretory phenotype

D:

Dasatinib

Q:

Quercetin

FFA:

Free fatty acid

ALT:

Alanine aminotransamine

TG:

Triglyceride

TCH:

Total cholesterol

H2O2 :

Hydrogen peroxide

BSA:

Bovine serum albumin

SA-β-gal:

Senescence-associated β-galactosidase

HPLC:

High-performance liquid chromatography

LE:

Loading efficiency

EE:

Entrapment efficiency

Cpt1α:

Carnitine palmitoyltransferase 1α

Ucp2:

Uncoupling protein 2

Accα:

Activated acetyl-CoA carboxylase

Acox1:

Acyl-CoA oxidase type 1

Scd1:

Stearoyl-CoA desaturase 1

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Funding

This work was supported by grants from the National Key Research and Development Program of China (2021YFA1100603), the National Natural Science Foundation of China (82071092, U21A20369), the Sichuan Science and Technology program (2023YFS0056, 2022YFS0126), and the Fundamental Research Funds for the Central Universities (2021SCU12140).

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Author notes

  1. Qi Tang and Xiaotao Xing contributed equally to this work.

Authors and Affiliations

  1. National Engineering Laboratory for Oral Regenerative Medicine & Engineering Research Center of Oral Translational Medicine, Ministry of Education & State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, West China School of Public Health & West China Fourth Hospital, Sichuan University, No.14, 3Rd Section Of Ren Min Nan Rd, Chengdu, 610041, Sichuan, China

    Qi Tang, Xiaotao Xing, Haisen Huang, Jian Yang, Maojiao Li, Xun Xu, Xin Gao, Cheng Liang, Weidong Tian & Li Liao

  2. Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Laboratory Center of Stomatology, College of Stomatology, Xi’an Jiaotong University, Xi’an, 710004, Shaanxi, China

    Xiaotao Xing

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  1. Qi Tang
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Correspondence to Weidong Tian or Li Liao.

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All animal procedures were performed under the relevant guidelines and approved by the Institutional Animal Care and Use Committee (IACUC) at West China Hospital of Stomatology (WCHSIRB-D-2019-034).

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Tang, Q., Xing, X., Huang, H. et al. Eliminating senescent cells by white adipose tissue–targeted senotherapy alleviates age-related hepatic steatosis through decreasing lipolysis. GeroScience 46, 3149–3167 (2024). https://doi.org/10.1007/s11357-024-01068-5

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