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Heterogeneity in Liver histopathology is associated with GSK-3b activity and Mitochondrial Dysfunction in End-stage Diabetic Rats on Differential Diets
Dong Jun Sung4,*, Jun-Ho Lee1,2, Soo-Bong Choi3, Mingli Jin5, Ju-Han Lee1, Ji-Young Mun6, Tae-Sook Hwang7, Sang-Don Han8, Inja Lim9, Young-Tae Ro1, Sung-Young Kim1, Jueng-Soo You1, Yun-Hee Noh1
1Department of Biochemistry, Konkuk University School of Medicine,
2C & R Research, C & R Research,
3Department of Internal Medicine, Konkuk University School of Medicine,
4Division of Sport and Health Science, Konkuk University,
5Gachon Institute of Pharmaceutical Sciences, Gachon University,
6Department of Structure and Function of Neural Network, Korea Brain Research Institute,
7Department of Pathology and 8Department of Medical Education, Konkuk University School of Medicine,
9Department of Physiology, Chung-Ang University
Abstract
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-3モ 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-3モ activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3モ 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-3モ activity and mitochondrial function in insulin-deficient state.
Abstract, Accepted Manuscript(in press) [Submitted on April 17, 2019, Accepted on June 9, 2019]
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