title: Phosphorylated heat shock protein 27 promotes lipid clearance in hepatic cells through interacting with STAT3 and activating autophagy.
abstract: Nonalcoholic fatty liver disease (NAFLD) has become the major liver disease worldwide. Recently, several studies have identified that the activation of autophagy attenuates hepatic steatosis. Heat shock protein 27 (Hsp27) is involved in autophagy in response to various stimuli. In this study, we demonstrate that phosphorylated Hsp27 stimulates autophagy and lipid droplet clearance and interacts with STAT3. In vivo study showed that high fat diet (HFD) feeding increased Hsp25 (mouse orthology of Hsp27) phosphorylation and autophagy in mouse livers. Inhibition of Hsp25 phosphorylation exacerbated HFD-induced hepatic steatosis in mice. In vitro study showed that palmitate-induced lipid overload in hepatic cells was enhanced by Hsp27 knockdown, KRIBB3 treatment and Hsp27-3A (non-phosphorylatable) overexpression but was prevented by Hsp27-WT (wild type) and Hsp27-3D (phosphomimetic) overexpression. Mechanism analysis demonstrated that palmitate could induce Hsp27 phosphorylation which promoted palmitate-induced autophagy. Phosphorylated Hsp27 interacted with STAT3 in response to palmitate treatment, and disrupted the STAT3/PKR complexes, facilitated PKR-dependent eIF2α phosphorylation, and thus stimulated autophagy. To conclude, our study provides a novel mechanism by which the phosphorylated Hsp27 promotes hepatic lipid clearance and suggests a new insight for therapy of steatotic diseases such as nonalcoholic fatty liver disease (NAFLD).
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China; Department of Biochemistry, Wannan Medical College, Wuhu, Anhui, PR China.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Song
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Xuan
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
authors.forename: Peiling
authors.initials: P
authors.lastname: Ben
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China. Electronic address: lanlei1978@gmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing, Jiangsu, PR China. Electronic address: lanluo@nju.edu.cn.
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.affiliation: Jiangsu Province Key Laboratory for Molecular Biotechnology, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China. Electronic address: yinzhimin@njnu.edu.cn.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D000840:Anisoles; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D059305:Diet, High-Fat; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007555:Isoxazoles; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C507623:5-(5-ethyl-2-hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl)isoxazole; D000840:Anisoles; D015852:Eukaryotic Initiation Factor-2; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D007555:Isoxazoles; D008055:Lipids; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D010168:Palmitates; D050796:STAT3 Transcription Factor; D019892:eIF-2 Kinase
keywords: Autophagy; Hepatic steatosis; Hsp27 phosphorylation; STAT3