4.7 Article

Modification of lysine deacetylation regulates curcumol-induced necroptosis through autophagy in hepatic stellate cells

Journal

PHYTOTHERAPY RESEARCH
Volume 36, Issue 6, Pages 2660-2676

Publisher

WILEY
DOI: 10.1002/ptr.7483

Keywords

autophagy; curcumol; hepatic stellate cell; liver fibrosis; necroptosis; Sirt1

Funding

  1. National Natural Science Foundation of China [82073914, 82000572, 81870423]
  2. Natural Science Foundation of Jiangsu Province [BK20200840]
  3. Major Project of the Natural Science Research of Jiangsu Higher Education Institutions [19KJA310005]
  4. General Projects of the Natural Science Research of Jiangsu Higher Education Institutions [20KJB310003]
  5. Joint Project of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica [JKLPSE202005]
  6. Natural Science Foundation of Nanjing University of Chinese Medicine [NZY82000572]
  7. Postgraduate Research & Practice Innovation Program of Government of Jiangsu Province [KYCX21_1732, SJCX20_0569, KYCX21_1637]
  8. Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine [2020YLXK022, 2020YLXK023]
  9. scientific instrument sharing platform of Nanjing University of Chinese Medicine

Ask authors/readers for more resources

This study found that curcumol can alleviate liver fibrosis by regulating necroptosis and autophagy in HSCs. This is achieved by activating Sirt1 to reduce the acetylation level of Atg5 and enhance the interaction between Atg5 and RIP1/RIP3.
The excessive deposition of extracellular matrix (ECM) is the main characteristic of liver fibrosis, and hepatic stellate cells (HSCs) are the main source of ECM. The removal of activated HSCs has a reversal effect on liver fibrosis. Western blot and MTT analysis indicated that curcumol could relieve hepatic fibrosis by promoting HSCs receptor-interacting protein kinase 1/3 (RIP1/RIP3)-dependent necroptosis. Importantly, autophagy flow was monitored by constructing the mRFP-GFP-LC3 plasmid, and it was found that curcumol cleared activated HSCs in a necroptosis manner that was dependent on autophagy. Our study suggested that the activation of necrosome formed by RIP1 and RIP3 depended on Atg5, and that autophagosomes were also necessary for curcumol-induced necroptosis. Furthermore, microscale thermophoresis and co-immunoprecipitation assay results proved that curcumol could target Sirt1 to regulate autophagy by reducing the acetylation level of Atg5. The HSCs-specific silencing of Sirt1 exacerbated CCl4-induced liver fibrosis in mice. The deacetylation of Atg5 not only accelerated the accumulation of autophagosomes but also enhanced the interaction between Atg5 and RIP1/RIP3 to induce necroptosis. Overall, our study indicated that curcumol could activate Sirt1 to promote Atg5 deacetylation and enhanced its protein-protein interaction function, thereby inducing autophagy and promoting the necroptosis of HSCs to reduce liver fibrosis.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available