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Sci Rep. 2016 Nov 22;5:37468. doi: 10.1038/srep37468.

Glutamate dehydrogenase activator BCH stimulating reductive amination prevents high fat/high fructose diet-induced steatohepatitis and hyperglycemia in C57BL/6J mice.

Author information

1
Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
2
Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
3
Department of Biomedical Science, The Graduate School Ajou University, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
4
National Efficacy Evaluation Center for Metabolic Disease Therapeutics, Lee Gil Ya Cancer and Diabetes Institute, Inchon, 406-840, Republic of Korea.
5
Department of Pathology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
6
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, 405-760, Republic of Korea.

Abstract

Individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) induced by high calorie western diet are characterized by enhanced lipogenesis and gluconeogenesis in the liver. Stimulation of reductive amination may shift tricarboxylic acid cycle metabolism for lipogenesis and gluconeogenesis toward glutamate synthesis with increase of NAD+/NADH ratio and thus, ameliorate high calorie diet-induced fatty liver and hyperglycemia. Stimulation of reductive amination through glutamate dehydrogenase (GDH) activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) reduced both de novo lipogenesis and gluconeogenesis but increased the activities of sirtuins and AMP-activated kinase in primary hepatocytes. Long-term BCH treatment improved most metabolic alterations induced by high fat/high fructose (HF/HFr) diet in C57BL/6J mice. BCH prevented HF/HFr-induced fat accumulation and activation of stress/inflammation signals such as phospho-JNK, phospho-PERK, phospho-p38, and phospho-NFκB in liver tissues. Furthermore, BCH treatment reduced the expression levels of inflammatory cytokines such as TNF-α and IL-1β in HF/HFr-fed mouse liver. BCH also reduced liver collagen and plasma levels of alanine transaminase and aspartate transaminase. On the other hand, BCH significantly improved fasting hyperglycemia and glucose tolerance in HF/HFr-fed mice. In conclusion, stimulation of reductive amination through GDH activation can be used as a strategy to prevent high calorie western diet-induced NAFLD and T2D.

PMID:
27874078
PMCID:
PMC5118703
DOI:
10.1038/srep37468
[Indexed for MEDLINE]
Free PMC Article

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