title: Lipid-Induced Endoplasmic Reticulum Stress Impairs Selective Autophagy at the Step of Autophagosome-Lysosome Fusion in Hepatocytes.
abstract: Blockage of hepatic autophagic degradation system occurs in obesity and is associated with the development of nonalcoholic fatty liver disease. However, the mechanism of this blockage remains unclear. We found a high-fat diet induced accumulation of autophagosomes in the mice livers. However, autophagy substrates such as p62 and ubiquitinated proteins also accumulated in the livers in this model. These findings indicate the possibility that a high-fat diet impairs autophagic flux in the liver. Then, to assess the autophagic flux in more detail, we performed analyses of autophagic flux in cultured hepatocytes exposed to monounsaturated fatty acids (FAs) or saturated FAs (SFAs). SFAs but not monounsaturated FAs suppressed degradation of contents in the autophagosomes. We analyzed each stage of the autophagy pathway (ie, autophagosome formation, autophagosome-lysosome fusion, lysosomal degradation) in cultured hepatocytes treated with monounsaturated FAs or SFAs and found that SFAs impaired autophagosome-lysosome fusion. This impairment occurred in an endoplasmic reticulum stress-dependent manner. Moreover, ubiquitin and p62-positive inclusions observed in high-fat diet-fed mice livers and SFA-treated cells were sequestered within autophagosomes. We also found that SFA-induced accumulation of Ser351-phosphorylated p62, which is indispensable for selective autophagy, further increased on administration of a lysosomal proteinase inhibitor. Although lipid-induced endoplasmic reticulum stress interferes with the autophagosome-lysosome fusion, selective autophagic sequestration of aggregated proteins is not inhibited.
authors.affiliation: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: koichiro@med.uoeh-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Miyagawa
authors.affiliation: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oe
authors.affiliation: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Honma
authors.affiliation: Department of Occupational Pneumology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Baba
authors.affiliation: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: msrharada@med.uoeh-u.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000473:pathology*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005227:Fatty Acids / Q000633:toxicity; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D008247:Lysosomes / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology / Q000503:physiopathology
chemical_list: D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated