Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities.
The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis.
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: tomaruu@med.hokudai.ac.jp.
Utano
U
Tomaru
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Satomi
S
Takahashi
Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
Akihiro
A
Ishizu
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Yukiko
Y
Miyatake
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Aya
A
Gohda
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Sayuri
S
Suzuki
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Ayako
A
Ono
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Jiro
J
Ohara
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Tomohisa
T
Baba
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.
Shigeo
S
Murata
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Keiji
K
Tanaka
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Masanori
M
Kasahara
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004722:Endoribonucleases / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008659:Metabolic Diseases / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology / Q000473:pathology; D000070780:Perilipin-2; D010641:Phenotype; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015431:Weight Loss / Q000502:physiology; D051020:bcl-X Protein / Q000378:metabolism
D007328:Insulin; D020738:Leptin; D008565:Membrane Proteins; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D051020:bcl-X Protein; D025821:Polyubiquitin; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D046988:Proteasome Endopeptidase Complex