title: Glutamate dehydrogenase activator BCH stimulating reductive amination prevents high fat/high fructose diet-induced steatohepatitis and hyperglycemia in C57BL/6J mice.
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.
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Yi
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.|Department of Biomedical Science, The Graduate School Ajou University, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Jong Gab
authors.initials: JG
authors.lastname: Jung
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.|Department of Biomedical Science, The Graduate School Ajou University, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Ik-Rak
authors.initials: IR
authors.lastname: Jung
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Maureen
authors.initials: M
authors.lastname: Shin
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Seok
authors.initials: S
authors.lastname: Kang
authors.affiliation: National Efficacy Evaluation Center for Metabolic Disease Therapeutics, Lee Gil Ya Cancer and Diabetes Institute, Inchon, 406-840, Republic of Korea.
authors.forename: Hyunhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Dae Jung
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kwon
authors.affiliation: National Efficacy Evaluation Center for Metabolic Disease Therapeutics, Lee Gil Ya Cancer and Diabetes Institute, Inchon, 406-840, Republic of Korea.|Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, 405-760, Republic of Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Kwan Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.|Department of Biomedical Science, The Graduate School Ajou University, Ajou University School of Medicine, Suwon, Gyunggi-do, 443-749, Republic of Korea.
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000586:Amination; D000598:Amino Acids, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D000073417:Dietary Sugars / Q000009:adverse effects*; D020536:Enzyme Activators / Q000494:pharmacology*; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D005632:Fructose / Q000009:adverse effects*; D005969:Glutamate Dehydrogenase / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism / Q000517:prevention & control*; D050155:Lipogenesis; D008297:Male; D008810:Mice, Inbred C57BL
chemical_list: D000598:Amino Acids, Cyclic; D004041:Dietary Fats; D000073417:Dietary Sugars; D020536:Enzyme Activators; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D005632:Fructose; D005969:Glutamate Dehydrogenase