Cargando…

Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabeti...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Jun-Ho, Choi, Soo-Bong, Sung, Dong-Jun, Jin, Mingli, Lee, Ju-Han, Mun, Ji-Young, Hwang, Tae-Sook, Han, Sang-Don, Ro, Young-Tae, Kim, Sung-Young, You, Jueng-Soo, Lim, Inja, Noh, Yun-Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Biochemistry and Molecular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061207/
https://www.ncbi.nlm.nih.gov/pubmed/31234955
http://dx.doi.org/10.5483/BMBRep.2020.53.2.114
_version_ 1783504360026669056
author Lee, Jun-Ho
Choi, Soo-Bong
Sung, Dong-Jun
Jin, Mingli
Lee, Ju-Han
Mun, Ji-Young
Hwang, Tae-Sook
Han, Sang-Don
Ro, Young-Tae
Kim, Sung-Young
You, Jueng-Soo
Lim, Inja
Noh, Yun-Hee
author_facet Lee, Jun-Ho
Choi, Soo-Bong
Sung, Dong-Jun
Jin, Mingli
Lee, Ju-Han
Mun, Ji-Young
Hwang, Tae-Sook
Han, Sang-Don
Ro, Young-Tae
Kim, Sung-Young
You, Jueng-Soo
Lim, Inja
Noh, Yun-Hee
author_sort Lee, Jun-Ho
collection PubMed
description While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague- Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorie-restricted (18R group), and 11 were both calorie- and protein-restricted with the low-protein diet (6R group). Overnight-fasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state.
format Online
Article
Text
id pubmed-7061207
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Korean Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-70612072020-03-19 Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets Lee, Jun-Ho Choi, Soo-Bong Sung, Dong-Jun Jin, Mingli Lee, Ju-Han Mun, Ji-Young Hwang, Tae-Sook Han, Sang-Don Ro, Young-Tae Kim, Sung-Young You, Jueng-Soo Lim, Inja Noh, Yun-Hee BMB Rep Article While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague- Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorie-restricted (18R group), and 11 were both calorie- and protein-restricted with the low-protein diet (6R group). Overnight-fasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state. Korean Society for Biochemistry and Molecular Biology 2020-02-29 2020-02-29 /pmc/articles/PMC7061207/ /pubmed/31234955 http://dx.doi.org/10.5483/BMBRep.2020.53.2.114 Text en Copyright © 2020 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Lee, Jun-Ho
Choi, Soo-Bong
Sung, Dong-Jun
Jin, Mingli
Lee, Ju-Han
Mun, Ji-Young
Hwang, Tae-Sook
Han, Sang-Don
Ro, Young-Tae
Kim, Sung-Young
You, Jueng-Soo
Lim, Inja
Noh, Yun-Hee
Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
title Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
title_full Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
title_fullStr Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
title_full_unstemmed Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
title_short Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
title_sort heterogeneity in liver histopathology is associated with gsk-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061207/
https://www.ncbi.nlm.nih.gov/pubmed/31234955
http://dx.doi.org/10.5483/BMBRep.2020.53.2.114
work_keys_str_mv AT leejunho heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT choisoobong heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT sungdongjun heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT jinmingli heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT leejuhan heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT munjiyoung heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT hwangtaesook heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT hansangdon heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT royoungtae heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT kimsungyoung heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT youjuengsoo heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT liminja heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets
AT nohyunhee heterogeneityinliverhistopathologyisassociatedwithgsk3bactivityandmitochondrialdysfunctioninendstagediabeticratsondifferentialdiets