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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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Related in: MedlinePlus

(A) The serum glucose levels, (B) serum insulin levels, (C) serum TG levels and (D) hepatic TG levels in the OVE26 mice as well as the FVB controls. (E) Hepatic lipid accumulation by Oil Red O staining. 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 1 month.
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Figure 3: (A) The serum glucose levels, (B) serum insulin levels, (C) serum TG levels and (D) hepatic TG levels in the OVE26 mice as well as the FVB controls. (E) Hepatic lipid accumulation by Oil Red O staining. 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 1 month.

Mentions: Because the metabolic disorder could be the central mechanism for diabetic liver injury and progression of steatohepatitis, blood glucose, insulin level, TG levels and hepatic lipid accumulation were further evaluated. Compared to FVB mice, blood glucose was significantly increased in the OVE26 mice. The blood glucose levels maintained at 375 - 425 mg/dL throughout entire experimental duration (Fig 3A). There was a significant decrease of serum insulin level in the OVE26 mice compared to the FVB controls (Fig 3B), which consisted to the previous reports 15;16. The serum TG level was slightly decreased in the OVE26 mice at month 1, but significantly increased from month 3 to month 8 compared to that in the FVB controls (Fig 3C). The hepatic TG level in OVE26 mice was slightly increased started at month 1, but became significantly increased from month 3 to month 8 compared to the FVB controls (Fig 3D). The hepatic lipid accumulation status was further evaluated in the liver tissues of OVE26 mice by Oil red O staining. As shown in Fig 3E, the positive staining was found in the OVE26 mice. The trend of lipid accumulating identified by Oil red O staining is consisted to liver TG level, which increased from month 3 to month 8.


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) The serum glucose levels, (B) serum insulin levels, (C) serum TG levels and (D) hepatic TG levels in the OVE26 mice as well as the FVB controls. (E) Hepatic lipid accumulation by Oil Red O staining. 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 1 month.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4400387&req=5

Figure 3: (A) The serum glucose levels, (B) serum insulin levels, (C) serum TG levels and (D) hepatic TG levels in the OVE26 mice as well as the FVB controls. (E) Hepatic lipid accumulation by Oil Red O staining. 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 1 month.
Mentions: Because the metabolic disorder could be the central mechanism for diabetic liver injury and progression of steatohepatitis, blood glucose, insulin level, TG levels and hepatic lipid accumulation were further evaluated. Compared to FVB mice, blood glucose was significantly increased in the OVE26 mice. The blood glucose levels maintained at 375 - 425 mg/dL throughout entire experimental duration (Fig 3A). There was a significant decrease of serum insulin level in the OVE26 mice compared to the FVB controls (Fig 3B), which consisted to the previous reports 15;16. The serum TG level was slightly decreased in the OVE26 mice at month 1, but significantly increased from month 3 to month 8 compared to that in the FVB controls (Fig 3C). The hepatic TG level in OVE26 mice was slightly increased started at month 1, but became significantly increased from month 3 to month 8 compared to the FVB controls (Fig 3D). The hepatic lipid accumulation status was further evaluated in the liver tissues of OVE26 mice by Oil red O staining. As shown in Fig 3E, the positive staining was found in the OVE26 mice. The trend of lipid accumulating identified by Oil red O staining is consisted to liver TG level, which increased from month 3 to month 8.

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