PMID- 34474107 OWN - NLM STAT- MEDLINE DCOM- 20210930 LR - 20210930 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 175 DP - 2021 Nov 1 TI - Elevated branched-chain alpha-keto acids exacerbate macrophage oxidative stress and chronic inflammatory damage in type 2 diabetes mellitus. PG - 141-154 LID - S0891-5849(21)00708-5 [pii] LID - 10.1016/j.freeradbiomed.2021.08.240 [doi] AB - AIMS: Chronic inflammation is a primary reason for type 2 diabetes mellitus (T2DM) and its complications, while disordered branched-chain amino acids (BCAA) metabolism is found in T2DM, but the link between BCAA catabolic defects and inflammation in T2DM remains elusive and needs to be investigated. METHODS: The changes in BCAA catabolism, inflammation, organ damage, redox status, and mitochondrial function in db/db mice with treatments of BCAA-overload or BCAA catabolism activator were analyzed in vivo. The changes in BCAA catabolic metabolism, as well as the direct effects of BCAAs/branched-chain alpha-keto acids (BCKAs) on cytokine release and redox status were also analyzed in primary macrophages in vitro. RESULTS: Inactivation of branched-chain a-ketoacid dehydrogenase (BCKDH) complex was found in multiple organs (liver, muscle and kidney) of db/db mice. Long-term high BCAA supplementation further increased BCKA levels, inflammation, tissue fibrosis (liver and kidney), and macrophage hyper-activation in db/db mice, while enhancing BCAA catabolism with pharmacological activator reduced these adverse effects in db/db mice. In vitro, the BCAA catabolism was unchanged in primary macrophages of db/db mice, and elevated BCKAs but not BCAAs promoted the cytokine production in primary macrophages. Moreover, BCKA stimulation was associated with increased mitochondrial oxidative stress and redox imbalance in macrophages and diabetic organs. CONCLUSION: Impaired BCAA catabolism is strongly associated with chronic inflammation and tissue damage in T2DM, and this effect is at least partly due to the BCKAs-induced macrophage oxidative stress. This study highlights that targeting BCAA catabolism is a potential strategy to attenuate T2DM and its complications. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Liu, Shuyun AU - Liu S AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Li, Ling AU - Li L AD - Division of Nephrology, West China Hospital, Sichuan University, Chengdu, China. FAU - Lou, Peng AU - Lou P AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Zhao, Meng AU - Zhao M AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Wang, Yizhuo AU - Wang Y AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Tang, Minghai AU - Tang M AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. FAU - Gong, Meng AU - Gong M AD - Laboratory of Clinical Proteomics and Metabolomics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Liao, Guangneng AU - Liao G AD - Animal Center, West China Hospital, Sichuan University, Chengdu, China. FAU - Yuan, Yujia AU - Yuan Y AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Li, Lan AU - Li L AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Zhang, Jie AU - Zhang J AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Chen, Younan AU - Chen Y AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Cheng, Jingqiu AU - Cheng J AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Lu, Yanrong AU - Lu Y AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. FAU - Liu, Jingping AU - Liu J AD - Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. Electronic address: liujingping@scu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210830 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Amino Acids, Branched-Chain) RN - 0 (Keto Acids) SB - IM MH - Amino Acids, Branched-Chain/metabolism MH - Animals MH - *Diabetes Mellitus, Type 2 MH - Keto Acids MH - Macrophages/metabolism MH - Mice MH - Oxidative Stress OTO - NOTNLM OT - BCAA catabolism OT - Inflammation OT - Macrophages OT - ROS OT - Type 2 diabetes mellitus EDAT- 2021/09/03 06:00 MHDA- 2021/10/01 06:00 CRDT- 2021/09/02 20:13 PHST- 2021/06/15 00:00 [received] PHST- 2021/08/26 00:00 [revised] PHST- 2021/08/30 00:00 [accepted] PHST- 2021/09/03 06:00 [pubmed] PHST- 2021/10/01 06:00 [medline] PHST- 2021/09/02 20:13 [entrez] AID - S0891-5849(21)00708-5 [pii] AID - 10.1016/j.freeradbiomed.2021.08.240 [doi] PST - ppublish SO - Free Radic Biol Med. 2021 Nov 1;175:141-154. doi: 10.1016/j.freeradbiomed.2021.08.240. Epub 2021 Aug 30.