ATG5-Mediated Autophagy May Inhibit Pyroptosis to Ameliorate Oleic Acid-Induced Hepatocyte Steatosis
- 1 December 2022
- journal article
- research article
- Published by Mary Ann Liebert Inc in DNA and Cell Biology
- Vol. 41 (12), 1038-1052
- https://doi.org/10.1089/dna.2022.0265
Abstract
Despite activated autophagy ameliorating hepatocyte steatosis and metabolic associated fatty liver disease (MAFLD), mechanisms underlying the beneficial roles of autophagy in hepatic deregulation of lipid metabolism remain undefined. We explored whether autophagy can ameliorate oleic acid (OA)-induced hepatic steatosis by suppressing pyroptosis. Pyroptosis is involved in hepatocyte steatosis induced by OA. In addition, autophagy flux was blocked in OA-treated hepatocytes. Treatment with OA induced lipid accumulation in liver cell line L-02, which was attenuated by rapamycin (Rap), an autophagy agonist, while aggravated by autophagy inhibitor bafilomycin A1 (Baf A1). Inversely, treatment with pyroptotic agonist Nigericin aggravated OA-induced hepatic steatosis, while pyroptosis antagonist disulfiram ameliorated this effect. Mechanistically, treatment with Rap downregulated the expression of pyroptosis-related proteins, including NLRP3, Caspase-1, IL-18, GSDMD expression evoked by OA, thus improving pyroptosis in hepatic steatosis. Significantly, overexpression of ATG5 obviously downregulated cleaved caspase-1 expressions without altering the total caspase1 expressions in hepatic cell steatosis. Taken together, our studies strongly demonstrated that the activation of ATG5 inhibits pyroptosis to improve hepatic steatosis and suggest autophagy activation as a potential therapeutic strategy for pyroptosis-mediated MAFLD.Keywords
This publication has 52 references indexed in Scilit:
- Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease interventionBiochemical Society Transactions, 2015
- Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLDCell Death & Disease, 2014
- Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in AtherogenesisPLOS ONE, 2014
- p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 geneCell Death & Differentiation, 2013
- Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma CellsSarcoma, 2013
- MicroRNA Modulation of Cholesterol HomeostasisArteriosclerosis, Thrombosis, and Vascular Biology, 2011
- Autophagy regulates lipid metabolismNature, 2009
- Cryopyrin activates the inflammasome in response to toxins and ATPNature, 2006
- Physiological and morphological evidences for the presence acidocalcisomes in Trypanosoma evansi: Single cell fluorescence and 31P NMR studiesMolecular and Biochemical Parasitology, 2002
- Ca2+/H+ exchange in acidic vacuoles of Trypanosoma bruceiBiochemical Journal, 1994