title: Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis.
abstract: Abnormal metabolism of nonesterified fatty acids (NEFAs) and their derivatives has been reported to be the main cause of intracellular lipotoxic injury. Normally, NEFAs are stored in lipid droplets (LDs) in the form of triglyceride (TG), which could reduce the lipotoxicity of cytosolic NEFAs. Previous studies have implicated that Perilipin 5 (Plin5), an LD-binding protein, regulates the storage and hydrolysis of TG in LD. However, its roles and underlying mechanisms in the liver remain unknown. Here we found that Plin5 expression was increased in steatotic livers. Using Plin5 knockout mice, we found that Plin5 deficiency resulted in reduced hepatic lipid content and smaller-sized LDs, which was due to the elevated lipolysis rate and fatty acid utilization. Plin5-deficient hepatocytes showed increased mitochondria proliferation, which could be explained by the increased expression and activity of PPARα stimulated by the increased NEFA levels. Meanwhile, Plin5-deficient livers also exhibited enhanced mitochondrial oxidative capacity. We also found that Plin5 deficiency induces lipotoxic injury in hepatocytes, attributed to lipid peroxidation. Mechanistically, we found that Plin5 blocks adipose triglyceride lipase (ATGL)-mediated lipolysis by competitively binding to comparative gene identification-58 (CGI-58) and disrupting the interaction between CGI-58 and ATGL.
  
  
  CONCLUSIONS
  Plin5 is an important protective factor against hepatic lipotoxicity induced by NEFAs generated from lipolysis. This provides an important new insight into the regulation of hepatic lipid storage and relation between lipid storage and lipotoxicity.
authors.affiliation: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xing
authors.initials: X
authors.lastname: Gao
authors.forename: Le
authors.initials: L
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Peizhen
authors.initials: P
authors.lastname: Hu
authors.forename: Xiumin
authors.initials: X
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Zengshan
authors.initials: Z
authors.lastname: Li
authors.forename: Huizhong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D059865:Endoplasmic Reticulum Stress; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D050356:Lipid Metabolism; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000737:chemistry / Q000502:physiology*; D047493:PPAR alpha / Q000502:physiology; D017434:Protein Structure, Tertiary
chemical_list: D005230:Fatty Acids, Nonesterified; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D047493:PPAR alpha; C551268:lipid storage droplet protein 5, mouse