title: Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB.
abstract: Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.|Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Longbin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Kou
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, China.
authors.forename: Zengxiang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Zhongni
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Electron Microscopic Center, Basic Medical Science College, Harbin Medical University, Harbin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.|Division of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yang
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000737:chemistry*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014465:Ultrasonics
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000873:Anthracenes; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018955:CD36 Antigens; D008055:Lipids; D017382:Reactive Oxygen Species; D051117:Scavenger Receptors, Class A; C064972:TFEB protein, human; D010569:Perylene; C004965:hypericin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase