Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice.
Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice.
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DOI：
10.1002/hep.24368
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发表时间：
2011-07
期刊：
影响因子：
13.5
通讯作者：
Lee, Amy S.
中科院分区：
文献类型：
--
作者：
Ji, Cheng;Kaplowitz, Neil;Lau, Mo Yin;Kao, Eddy;Petrovic, Lydia M.;Lee, Amy S.
The endoplasmic reticulum (ER) chaperone protein glucose-regulated protein 78 (GRP78/BiP) is a master regulator of ER homeostasis and stress response which are implicated in pathogenesis of metabolic disorders. By applying the LoxP-Cre strategy, we generated mice with liver specific GRP78 loss. Our studies using this novel mouse model revealed that liver GRP78 was required for neonatal survival and more than 50% loss of GRP78 in the adult liver caused ER stress response and dilation of ER compartment, accompanied by onset of apoptosis, suggesting critical involvement of GRP78 in maintaining hepatocyte ER homeostasis and viability. Further, these mice exhibited elevation of serum alanine aminotransferase and fat accumulation in the liver, and were sensitized to a variety of acute and chronic hepatic disorders by alcohol, high fat diet, drugs and toxins, which were alleviated by simultaneous administration of the molecular chaperone, 4-phenylbutyrate. Analysis by microarray followed by 2D protein profile revealed major perturbation of unfolded protein response (UPR) targets and common enzymes/factors in lipogenesis as well as new factors including liver major urinary proteins, fatty acid binding proteins, adipose differentiation-related protein, cysteine-rich with EGF-like domains 2 (Creld2), nuclear protein 1, and growth differentiation factor 15 (gdf15) possibly contributing to liver steatosis or fibrosis under ER stress. Our findings underscore the importance of GRP78 in managing the physiological client protein load and suppressing apoptosis in hepatocytes, supporting the pathologic role of ER stress in the evolution of fatty liver and disease under adverse conditions of drugs, diet, toxins and alcohol.
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影响因子：
3.9
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.0807691105
发表时间：
2008-12-09
影响因子：
11.1
作者：
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通讯作者：
Lee, Amy S.
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作者：
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影响因子：
29.4
作者：
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通讯作者：
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