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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) detection of neutrophils by chloroacetate esterase staining in liver tissues. Arrow: positive stained neutrophils. m: mouse age in months. OVE: OVE26. (B) Western blot analysis of proinflammatory cytokines (TGFβ, TNFα, ICAM1, and CTGF) in the liver tissues from OVE26 mice as well as the FVB controls. Data are presented as mean ± SD. * P<0.05 compared to FVB controls; & P <0.05 compared to OVE mice aged 3 month.
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Figure 2: (A) detection of neutrophils by chloroacetate esterase staining in liver tissues. Arrow: positive stained neutrophils. m: mouse age in months. OVE: OVE26. (B) Western blot analysis of proinflammatory cytokines (TGFβ, TNFα, ICAM1, and CTGF) in the liver tissues from OVE26 mice as well as the FVB controls. Data are presented as mean ± SD. * P<0.05 compared to FVB controls; & P <0.05 compared to OVE mice aged 3 month.

Mentions: Diabetes causes damages in multiple organs, more common in the heart and kidney, because of the metabolic syndrome. However, the diabetes associated metabolic liver injury was received less attention previously. We evaluated the dynamic changes in term of liver injury in the diabetic OVE26 mice. The H&E results showed that there was no significantly morphological abnormality at month 1 and 3, but abnormal morphological at month 5 and more severe morphological abnormality at month 8 in the liver from OVE26 mice. The pathological study revealed that there were a multifocal distribution of irregular, lager volume and empty bubble-like lipid drops inside hepatocytes. Steatohepatitis was characterized by inflammatory infiltration and lipid drops in OVE26 mice compared to the FVB controls (Fig 1A). There was a slight increase of serum ALT level in the OVE26 mice aged month 1, however the levels of serum ALT were significantly increased in the OVE26 mice aged 3, 5 and 8 months (Fig 1B).The increased levels of serum ALT activity is consistent with the severity of steatohepatitis. Naphthol-AS D chloroacetate was used as the substrate to detect esterase presented in the activated neutrophils. Increased number of activated neutrophils was detected in the liver tissues from OVE26 mice at both month 5 and month 8, implying proinflammatory state in the liver tissues of OVE26 mice at later stages (Fig 2A). Interestingly, the neutrophils showed a pattern of aggregated distribution in the liver tissues of the OVE26 mice at month 8, consisting to the severe morphological abnormalities. Further analysis indicated that protein levels of proinflammatory cytokines (TGFβ, TNFα, ICAM1, and CTGF) by Western blot were also increased in the liver tissues of OVE26 mice in later stages (Fig 2B).


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) detection of neutrophils by chloroacetate esterase staining in liver tissues. Arrow: positive stained neutrophils. m: mouse age in months. OVE: OVE26. (B) Western blot analysis of proinflammatory cytokines (TGFβ, TNFα, ICAM1, and CTGF) in the liver tissues from OVE26 mice as well as the FVB controls. Data are presented as mean ± SD. * P<0.05 compared to FVB controls; & P <0.05 compared to OVE mice aged 3 month.
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Related In: Results  -  Collection

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Figure 2: (A) detection of neutrophils by chloroacetate esterase staining in liver tissues. Arrow: positive stained neutrophils. m: mouse age in months. OVE: OVE26. (B) Western blot analysis of proinflammatory cytokines (TGFβ, TNFα, ICAM1, and CTGF) in the liver tissues from OVE26 mice as well as the FVB controls. Data are presented as mean ± SD. * P<0.05 compared to FVB controls; & P <0.05 compared to OVE mice aged 3 month.
Mentions: Diabetes causes damages in multiple organs, more common in the heart and kidney, because of the metabolic syndrome. However, the diabetes associated metabolic liver injury was received less attention previously. We evaluated the dynamic changes in term of liver injury in the diabetic OVE26 mice. The H&E results showed that there was no significantly morphological abnormality at month 1 and 3, but abnormal morphological at month 5 and more severe morphological abnormality at month 8 in the liver from OVE26 mice. The pathological study revealed that there were a multifocal distribution of irregular, lager volume and empty bubble-like lipid drops inside hepatocytes. Steatohepatitis was characterized by inflammatory infiltration and lipid drops in OVE26 mice compared to the FVB controls (Fig 1A). There was a slight increase of serum ALT level in the OVE26 mice aged month 1, however the levels of serum ALT were significantly increased in the OVE26 mice aged 3, 5 and 8 months (Fig 1B).The increased levels of serum ALT activity is consistent with the severity of steatohepatitis. Naphthol-AS D chloroacetate was used as the substrate to detect esterase presented in the activated neutrophils. Increased number of activated neutrophils was detected in the liver tissues from OVE26 mice at both month 5 and month 8, implying proinflammatory state in the liver tissues of OVE26 mice at later stages (Fig 2A). Interestingly, the neutrophils showed a pattern of aggregated distribution in the liver tissues of the OVE26 mice at month 8, consisting to the severe morphological abnormalities. Further analysis indicated that protein levels of proinflammatory cytokines (TGFβ, TNFα, ICAM1, and CTGF) by Western blot were also increased in the liver tissues of OVE26 mice in later stages (Fig 2B).

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