title: Acute accumulation of free cholesterol induces the degradation of perilipin 2 and Rab18-dependent fusion of ER and lipid droplets in cultured human hepatocytes.
abstract: Dysregulated hepatic cholesterol homeostasis with free cholesterol accumulation in the liver is relevant to the pathogenesis of nonalcoholic steatohepatitis, contributing to the chronicity of liver toxicity. Here we examined the effect of free cholesterol accumulation on the morphology and biochemical properties of lipid droplets (LDs) in cultured hepatocytes. Acute free cholesterol accumulation induced the fusion of LDs, followed by degradation of the coat protein of LDs, perilipin 2 (PLIN2; also called adipophilin or adipose differentiation-related protein), and association of apolipoprotein B 100 (ApoB 100) to LDs. The degradation of PLIN2 was inhibited by inhibitors of ubiquitination, autophagy, and protein synthesis. The results indicate that association of ApoB 100 with LDs is dependent on the activity of low-molecular weight GTP-binding protein Rab18 and highlight the role of LDs as targets of free cholesterol toxicity in hepatocytes.
authors: INSERM-RIKEN Lipidomics Unit, Université Lyon 1, 69621 Villeurbanne, France.|INSERM U1060, INSA-Lyon, Université Lyon 1, 69621 Villeurbanne, France.|Lipid Biology Laboratory, RIKEN, Wako 351-0198, Japan.
authors: Asami
authors: A
authors: Makino
authors: INSERM-RIKEN Lipidomics Unit, Université Lyon 1, 69621 Villeurbanne, France.|INSERM U1060, INSA-Lyon, Université Lyon 1, 69621 Villeurbanne, France.|Lipid Biology Laboratory, RIKEN, Wako 351-0198, Japan.
authors: Françoise
authors: F
authors: Hullin-Matsuda
authors: Lipid Biology Laboratory, RIKEN, Wako 351-0198, Japan.
authors: Motohide
authors: M
authors: Murate
authors: Lipid Biology Laboratory, RIKEN, Wako 351-0198, Japan.
authors: Mitsuhiro
authors: M
authors: Abe
authors: Lipid Biology Laboratory, RIKEN, Wako 351-0198, Japan.
authors: Nario
authors: N
authors: Tomishige
authors: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan.
authors: Mitsunori
authors: M
authors: Fukuda
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors: Shizuya
authors: S
authors: Yamashita
authors: Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Toyoshi
authors: T
authors: Fujimoto
authors: INSERM-RIKEN Lipidomics Unit, Université Lyon 1, 69621 Villeurbanne, France.|INSERM U1060, INSA-Lyon, Université Lyon 1, 69621 Villeurbanne, France.
authors: Hubert
authors: H
authors: Vidal
authors: INSERM-RIKEN Lipidomics Unit, Université Lyon 1, 69621 Villeurbanne, France.|INSERM U1060, INSA-Lyon, Université Lyon 1, 69621 Villeurbanne, France.
authors: Michel
authors: M
authors: Lagarde
authors: INSERM-RIKEN Lipidomics Unit, Université Lyon 1, 69621 Villeurbanne, France.|INSERM U1060, INSA-Lyon, Université Lyon 1, 69621 Villeurbanne, France.
authors: Isabelle
authors: I
authors: Delton
authors: INSERM-RIKEN Lipidomics Unit, Université Lyon 1, 69621 Villeurbanne, France kobayasi@riken.jp toshihide.kobayashi@unistra.fr.|INSERM U1060, INSA-Lyon, Université Lyon 1, 69621 Villeurbanne, France.|Lipid Biology Laboratory, RIKEN, Wako 351-0198, Japan.|UMR 7213 CNRS, University of Strasbourg, 67401 Illkirch, France.
authors: Toshihide
authors: T
authors: Kobayashi
mesh_terms: D053299:Apolipoprotein B-100 / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D018929:Cell Culture Techniques; D002784:Cholesterol / Q000378:metabolism* / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism* / Q000502:physiology*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D000070780:Perilipin-2 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins
chemical_list: D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D008055:Lipids; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D010750:Phosphoproteins; C484168:RAB18 protein, human; D002784:Cholesterol; D020691:rab GTP-Binding Proteins