Limits...
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.

Show MeSH

Related in: MedlinePlus

(A) Quantitative analysis of apoptotic cell death in the liver tissues by TUNEL staining. (B and C) The expressions of Bax, Bcl-2, and caspase-8 were detected by Western blotting assay. (D) Quantitative analysis of hepatocytes proliferation and representative images of positive PCNA staining. m: mouse age in months. OVE: OVE26. Data are presented as mean ± SD (n = 7 in each group). * P<0.05 compared to FVB controls.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4400387&req=5

Figure 6: (A) Quantitative analysis of apoptotic cell death in the liver tissues by TUNEL staining. (B and C) The expressions of Bax, Bcl-2, and caspase-8 were detected by Western blotting assay. (D) Quantitative analysis of hepatocytes proliferation and representative images of positive PCNA staining. m: mouse age in months. OVE: OVE26. Data are presented as mean ± SD (n = 7 in each group). * P<0.05 compared to FVB controls.

Mentions: ER stress-activated autophagy could be associated with various signaling pathways regarding the hepatic damage and fatty liver progression. The above findings prompted us to further explore the events regarding metabolic liver injury underlying the ER stress and autophagy dysfunction. We sought to examine the caspase-dependent apoptotic cell death in the liver of OVE26 mice. Surprisingly, inhibition of apoptosis was fund in the OVE26 mice (Fig 6A). Interestingly, analysis of Bcl-2, Bax and caspase-8, as one of mitochondrial cell death pathway, disclosed a synergistic increase in the Bcl-2/Bax ratio (Fig 6B) and decrease of caspase-8 (Fig 6C) in the OVE26 mice aged from 3 months to 8 months. The exact mechanism for the suppression of apoptosis in the liver under diabetic circumstance needs to be further studied. However, our data suggested that the dysfunction of autophagy may, at least partly, keep the hepatocytes from autophagy-related apoptotic cell death in the later stage of diabetes in the OVE26 mice. In contrast, a significant increase of PCNA expression by immunohistochemical staining was observed in the liver tissues of OVE26 mice (Fig 6D). PCNA helps hold DNA polymerase epsilon to DNA 28. Since DNA polymerase epsilon is involved in resynthesis of excised damaged DNA strands during DNA repair 29, increased PCNA levels suggesting repetitive hepatocytes damage and DNA repair happened during metabolic liver injury by diabetes.


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) Quantitative analysis of apoptotic cell death in the liver tissues by TUNEL staining. (B and C) The expressions of Bax, Bcl-2, and caspase-8 were detected by Western blotting assay. (D) Quantitative analysis of hepatocytes proliferation and representative images of positive PCNA staining. m: mouse age in months. OVE: OVE26. Data are presented as mean ± SD (n = 7 in each group). * P<0.05 compared to FVB controls.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: (A) Quantitative analysis of apoptotic cell death in the liver tissues by TUNEL staining. (B and C) The expressions of Bax, Bcl-2, and caspase-8 were detected by Western blotting assay. (D) Quantitative analysis of hepatocytes proliferation and representative images of positive PCNA staining. m: mouse age in months. OVE: OVE26. Data are presented as mean ± SD (n = 7 in each group). * P<0.05 compared to FVB controls.
Mentions: ER stress-activated autophagy could be associated with various signaling pathways regarding the hepatic damage and fatty liver progression. The above findings prompted us to further explore the events regarding metabolic liver injury underlying the ER stress and autophagy dysfunction. We sought to examine the caspase-dependent apoptotic cell death in the liver of OVE26 mice. Surprisingly, inhibition of apoptosis was fund in the OVE26 mice (Fig 6A). Interestingly, analysis of Bcl-2, Bax and caspase-8, as one of mitochondrial cell death pathway, disclosed a synergistic increase in the Bcl-2/Bax ratio (Fig 6B) and decrease of caspase-8 (Fig 6C) in the OVE26 mice aged from 3 months to 8 months. The exact mechanism for the suppression of apoptosis in the liver under diabetic circumstance needs to be further studied. However, our data suggested that the dysfunction of autophagy may, at least partly, keep the hepatocytes from autophagy-related apoptotic cell death in the later stage of diabetes in the OVE26 mice. In contrast, a significant increase of PCNA expression by immunohistochemical staining was observed in the liver tissues of OVE26 mice (Fig 6D). PCNA helps hold DNA polymerase epsilon to DNA 28. Since DNA polymerase epsilon is involved in resynthesis of excised damaged DNA strands during DNA repair 29, increased PCNA levels suggesting repetitive hepatocytes damage and DNA repair happened during metabolic liver injury by diabetes.

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