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1.
FASEB J ; 35(4): e21223, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715196

RESUMO

The role of Sidt2 in the process of glucose and lipid metabolism has been recently reported. However, whether Sidt2 is involved in the metabolic regulation in skeletal muscle remains unknown. In this study, for the first time, using skeletal muscle-selective Sidt2 knockout mice, we found that Sidt2 was vital for the quality control of mitochondria in mouse skeletal muscle. These mice showed significantly reduced muscle tolerance and structurally abnormal mitochondria. Deletion of the Sidt2 gene resulted in decreased expression of mitochondrial fusion protein 2 (Mfn2) and Dynamin-related protein 1 (Drp1), as well as peroxisome proliferator-activated receptor γ coactivator-1 (PGC1-α). In addition, the clearance of damaged mitochondria in skeletal muscle was inhibited upon Sidt2 deletion, which was caused by blockade of autophagy flow. Mechanistically, the fusion of autophagosomes and lysosomes was compromised in Sidt2 knockout skeletal muscle cells. In summary, the deletion of the Sidt2 gene not only interfered with the quality control of mitochondria, but also inhibited the clearance of mitochondria and caused the accumulation of a large number of damaged mitochondria, ultimately leading to the abnormal structure and function of skeletal muscle.


Assuntos
Membrana Celular , Lisossomos , Músculo Esquelético/metabolismo , Proteínas de Transporte de Nucleotídeos/metabolismo , Animais , Autofagia/fisiologia , Linhagem Celular , Regulação da Expressão Gênica , Predisposição Genética para Doença , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/citologia , Doenças Musculares/genética , Proteínas de Transporte de Nucleotídeos/genética
2.
Biochem Biophys Res Commun ; 476(4): 326-332, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27233614

RESUMO

Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2(-/-) mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2(-/-) mice, there were obvious fat degeneration and inflammatory changes. Almost all of the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2(-/-) mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2(-/-) mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2(-/-) mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2(-/-) mice had spontaneous nonalcoholic fatty liver disease (NAFLD) accompanied by ERS. In summary, as a lysosomal membrane protein, Sidt2 plays an important role in the pathogenesis of NAFLD, and ERS may mediate the occurrence and development of this disease in Sdit2 deficiency mice.


Assuntos
Estresse do Retículo Endoplasmático , Metabolismo dos Lipídeos , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Feminino , Expressão Gênica , Lipídeos/sangue , Lipídeos/genética , Fígado/patologia , Fígado/ultraestrutura , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas de Transporte de Nucleotídeos
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