p62/Sqstm1 rescue in muscle retards the progression of steatohepatitis in p62/Sqstm1-null mice fed a high-fat diet.
p62/Sqstm1 rescue in muscle retards the progression of steatohepatitis in p62/Sqstm1-null mice fed a high-fat diet.
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DOI：
10.3389/fphys.2022.993995
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发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
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简介：肥胖是许多疾病的危险因素，因为它会导致骨骼肌质量减少，并促进胰岛素抵抗。p62/Sqstm 1-敲除小鼠是代谢综合征的模型;显示肥胖、胰岛素抵抗和非酒精性脂肪肝（NAFL）;并且响应于高脂肪饮食（HFD）的喂养而发展非酒精性脂肪性肝炎（NASH）。这些表型表明，肌肉p62可以防止肥胖引起的肌肉功能障碍。在本研究中，我们的目的是确定肌肉p62对骨骼肌质量，肌肉力量，胰岛素抵抗和NASH病理的影响。 研究方法：我们产生了肌肉特异性p62基因拯救小鼠（p62-mRes），其仅在肌肉中表达p62，并且使用cre/loxp系统从p62敲除小鼠（p62 KIKI）衍生而来。p62 KIKI和p62-mRes小鼠喂食HFD 20周，并比较它们的表型。 结果：HFD喂养导致p62 KIKI和p62-mRes小鼠严重肥胖，但肌肉p62对体重没有影响。四肢骨骼肌质量，握力，和肌纤维的横截面积在p62-mRes小鼠高于p62 KIKI。p62-mRes小鼠的葡萄糖耐量和胰岛素敏感性也是上级的。在p62-mRes小鼠中，促进肌肉蛋白质合成的雷帕霉素的机械靶点和骨骼肌中的葡萄糖转运蛋白GLUT 4的蛋白质表达更高。当喂食HFD时，p62 KIKI小鼠发展为严重的NASH，但是肌肉中的p62基因拯救延缓了NASH的进展，并且编码促进肝纤维化的因子的Tgf-β1的表达减少。 结论：在全身p62敲除小鼠中拯救肌肉特异性p62改善胰岛素抵抗并延缓由全身p62消融引起的NASH进展。
Introduction: Obesity is a risk factor for many diseases because it leads to a reduction in skeletal muscle mass and promotes insulin resistance. p62/Sqstm1-knockout mice are a model of metabolic syndrome; show obesity, insulin resistance, and non-alcoholic fatty liver (NAFL); and develop non-alcoholic steatohepatitis (NASH) in response to the feeding of a high-fat diet (HFD). These phenotypes suggest that muscle p62 may prevent obesity-induced muscle dysfunction. In the present study, we aimed to determine the effects of muscle p62 on skeletal muscle mass, muscle strength, insulin resistance, and NASH pathology. Methods: We generated muscle-specific p62 gene rescue mice (p62-mRes), which express p62 only in muscle and were derived from p62-knock out mice (p62 KIKI ) using the cre/loxp system. p62 KIKI and p62-mRes mice were fed an HFD for 20 weeks and their phenotypes were compared. Results: HFD-feeding caused severe obesity in both p62 KIKI and p62-mRes mice, but there was no effect of muscle p62 on body mass. Limb skeletal muscle mass, grip strength, and the cross-sectional area of muscle fibers were higher in p62-mRes mice than in p62 KIKI . The glucose tolerance and insulin sensitivity of the p62-mRes mice were also superior. The protein expression of mechanistic target of rapamycin, which promotes muscle protein synthesis, and GLUT4, a glucose transporter in skeletal muscle, were higher in the p62-mRes mice. p62 KIKI mice developed severe NASH when fed an HFD, but the progression of NASH was retarded by p62 gene rescue in muscle, and the expression of Tgf-β1, which encodes a factor that promotes hepatic fibrosis, was reduced. Conclusion: Rescue of muscle-specific p62 in the whole-body p62 knock-out mice ameliorates the insulin resistance and retards the progression of NASH caused by systemic p62 ablation.
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DOI：
10.1016/j.jhepr.2021.100253
发表时间：
2021-06
期刊：
JHEP reports : innovation in hepatology
影响因子：
--
作者：
Oh S;Tsujimoto T;Kim B;Uchida F;Suzuki H;Iizumi S;Isobe T;Sakae T;Tanaka K;Shoda J
通讯作者：
Shoda J
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
15.9
作者：
Mueller, Timo D.;Lee, Sang Jun;Tschoep, Matthias H.
通讯作者：
Tschoep, Matthias H.
DOI：
10.1002/jcsm.12045
发表时间：
2016-05
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Sakuma K;Kinoshita M;Ito Y;Aizawa M;Aoi W;Yamaguchi A
通讯作者：
Yamaguchi A
影响因子：
4.2
作者：
Okada, Kosuke;Yanagawa, Toru;Ishii, Tetsuro
通讯作者：
Ishii, Tetsuro