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ER stress and autophagy dysfunction contribute to fatty liver in diabetic mice.

Zhang Q, Li Y, Liang T, Lu X, Zhang C, Liu X, Jiang X, Martin RC, Cheng M, Cai L - Int. J. Biol. Sci. (2015)

Bottom Line: Likewise, autophagy functioned well in the early stage but suppressed in the later stage.The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition.We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Infectious Diseases, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China, 550004 ; 4. Kosair Children's Hospital Research Institute, the Department of Pediatrics of the University of Louisville, Louisville, KY 40202, USA.

ABSTRACT
Diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are often identified in patients simultaneously. Recent evidence suggests that endoplasmic reticulum (ER) stress and autophagy dysfunction play an important role in hepatocytes injury and hepatic lipid metabolism, however the mechanistic interaction between diabetes and NAFLD is largely unknown. In this study, we used a diabetic mouse model to study the interplay between ER stress and autophagy during the pathogenic transformation of NAFLD. The coexist of inflammatory hepatic injury and hepatic accumulation of triglycerides (TGs) stored in lipid droplets indicated development of steatohepatitis in the diabetic mice. The alterations of components for ER stress signaling including ATF6, GRP78, CHOP and caspase12 indicated increased ER stress in liver tissues in early stage but blunted in the later stage during the development of diabetes. Likewise, autophagy functioned well in the early stage but suppressed in the later stage. The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition. We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.

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(A-D) The expression of GRP78, ATF6, CHOP and caspase-12 were detected by Western blotting assay. Data are presented as mean ± SD. m: mouse age in months. OVE: OVE26. * P<0.05 compared to FVB controls. & P <0.05 compared to OVE26 mice aged 3 month. # P <0.05 compared to OVE mice aged 5 month.
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Figure 4: (A-D) The expression of GRP78, ATF6, CHOP and caspase-12 were detected by Western blotting assay. Data are presented as mean ± SD. m: mouse age in months. OVE: OVE26. * P<0.05 compared to FVB controls. & P <0.05 compared to OVE26 mice aged 3 month. # P <0.05 compared to OVE mice aged 5 month.

Mentions: To investigate a putative link between the liver metabolic injury and hepatic ER stress, we firstly examined the expression of GRP78 and ATF6, which were crucial not only in ER stress but also lipid biogenesis 18;19. The ER protein chaperone, GRP78 protein level was significantly increased at month 5 but significantly decreased at month 8 (Fig 4A), suggesting loss of the ability to active the ER stress sense proteins such as ATF6 at the later stage of diabetes. As expected, ATF6 protein level was significantly increased in OVE26 mice at month 5 but decreased at month 8, which is consisting to the expression pattern of GRP78 (Fig 4B). The deficiency of both ATF6 and GRP78 indicated that cells were unable to restore the unfolded proteins in the ER lumen in later stage of diabetes. As we know, excessive or adverse stress to the ER could trigger apoptosis in the cells, we further investigated two important apoptotic executioners, CHOP and caspase-12, which are closely related to ER stress. CHOP is a member of the C/EBP family of transcription factors. Under physiological conditions, the expression of CHOP is very low, but it will be significantly up-regulated in response to ER stress 20. Caspase-12 located on ER and can be specifically activated by stimuli that elicit ER stress21. Importantly, CHOP and caspase-12 are critical executioners involved in the ER stress and mediated apoptosis. Our results indicated that the expression of CHOP (Fig 4C) was significantly increased at month 8, similarly, caspase-12 expression (Fig 4D) was also increased at month 8. These results indicated that the activation of the UPR following ER stress happened in early stage of diabetes in the OVE26 mice. However, the loss of the ability to restore the unfolded or misfolded proteins in the ER lumen happened in the later stag of diabetes, and trigged apoptotic mediators such as CHOP and caspase-12 to remove the abnormal cells. In this circumstance, the clearance mechanism such as autophagy to keep cellular homeostasis could be involved during progression of metabolic disorder in the diabetic liver.


ER stress and autophagy dysfunction contribute to fatty liver in diabetic mice.

Zhang Q, Li Y, Liang T, Lu X, Zhang C, Liu X, Jiang X, Martin RC, Cheng M, Cai L - Int. J. Biol. Sci. (2015)

(A-D) The expression of GRP78, ATF6, CHOP and caspase-12 were detected by Western blotting assay. Data are presented as mean ± SD. m: mouse age in months. OVE: OVE26. * P<0.05 compared to FVB controls. & P <0.05 compared to OVE26 mice aged 3 month. # P <0.05 compared to OVE mice aged 5 month.
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Related In: Results  -  Collection

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Figure 4: (A-D) The expression of GRP78, ATF6, CHOP and caspase-12 were detected by Western blotting assay. Data are presented as mean ± SD. m: mouse age in months. OVE: OVE26. * P<0.05 compared to FVB controls. & P <0.05 compared to OVE26 mice aged 3 month. # P <0.05 compared to OVE mice aged 5 month.
Mentions: To investigate a putative link between the liver metabolic injury and hepatic ER stress, we firstly examined the expression of GRP78 and ATF6, which were crucial not only in ER stress but also lipid biogenesis 18;19. The ER protein chaperone, GRP78 protein level was significantly increased at month 5 but significantly decreased at month 8 (Fig 4A), suggesting loss of the ability to active the ER stress sense proteins such as ATF6 at the later stage of diabetes. As expected, ATF6 protein level was significantly increased in OVE26 mice at month 5 but decreased at month 8, which is consisting to the expression pattern of GRP78 (Fig 4B). The deficiency of both ATF6 and GRP78 indicated that cells were unable to restore the unfolded proteins in the ER lumen in later stage of diabetes. As we know, excessive or adverse stress to the ER could trigger apoptosis in the cells, we further investigated two important apoptotic executioners, CHOP and caspase-12, which are closely related to ER stress. CHOP is a member of the C/EBP family of transcription factors. Under physiological conditions, the expression of CHOP is very low, but it will be significantly up-regulated in response to ER stress 20. Caspase-12 located on ER and can be specifically activated by stimuli that elicit ER stress21. Importantly, CHOP and caspase-12 are critical executioners involved in the ER stress and mediated apoptosis. Our results indicated that the expression of CHOP (Fig 4C) was significantly increased at month 8, similarly, caspase-12 expression (Fig 4D) was also increased at month 8. These results indicated that the activation of the UPR following ER stress happened in early stage of diabetes in the OVE26 mice. However, the loss of the ability to restore the unfolded or misfolded proteins in the ER lumen happened in the later stag of diabetes, and trigged apoptotic mediators such as CHOP and caspase-12 to remove the abnormal cells. In this circumstance, the clearance mechanism such as autophagy to keep cellular homeostasis could be involved during progression of metabolic disorder in the diabetic liver.

Bottom Line: Likewise, autophagy functioned well in the early stage but suppressed in the later stage.The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition.We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Infectious Diseases, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China, 550004 ; 4. Kosair Children's Hospital Research Institute, the Department of Pediatrics of the University of Louisville, Louisville, KY 40202, USA.

ABSTRACT
Diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are often identified in patients simultaneously. Recent evidence suggests that endoplasmic reticulum (ER) stress and autophagy dysfunction play an important role in hepatocytes injury and hepatic lipid metabolism, however the mechanistic interaction between diabetes and NAFLD is largely unknown. In this study, we used a diabetic mouse model to study the interplay between ER stress and autophagy during the pathogenic transformation of NAFLD. The coexist of inflammatory hepatic injury and hepatic accumulation of triglycerides (TGs) stored in lipid droplets indicated development of steatohepatitis in the diabetic mice. The alterations of components for ER stress signaling including ATF6, GRP78, CHOP and caspase12 indicated increased ER stress in liver tissues in early stage but blunted in the later stage during the development of diabetes. Likewise, autophagy functioned well in the early stage but suppressed in the later stage. The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition. We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.

Show MeSH
Related in: MedlinePlus