PMID- 38061536 OWN - NLM STAT- MEDLINE DCOM- 20231225 LR - 20240102 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 336 DP - 2024 Jan 1 TI - Treatment with a new barbituric acid derivative suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice. PG - 122327 LID - S0024-3205(23)00962-1 [pii] LID - 10.1016/j.lfs.2023.122327 [doi] AB - INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, often accompanied by obesity, diabetes, and increased risks of depression and anxiety. Currently, there are no FDA-approved drugs to treat NAFLD and its related systemic symptoms. Previously, we identified a new barbituric acid derivative (BA-5) that expressed effectiveness against fibrosis and drug-resistant hepatocellular carcinoma. AIMS: This study investigated the potential of BA-5 against high-fat diet (HFD)-induced NAFLD and mood disorders in mice. MAIN METHODS: Six-weeks-old male C57BL/6 mice were fed with a 45 % HFD for 8 weeks to induce NAFLD and associated metabolic disorders. Mice were treated with a BA-5 and the therapeutic effects and the underlying molecular mechanisms were investigated. KEY FINDINGS: Administration of BA-5 significantly reduced serum levels of alanine aminotransferase (ALT), low-density lipoprotein (LDL), fatty acids (FA), and triglycerides (TG) in HFD-fed mice. BA-5 treatment decreased expressions of hepatic lipogenesis-related markers (acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and ATP-citrate lyase (ACLY)), increased fatty acid oxidation markers (carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1)), and attenuated hepatic fat accumulation in HFD-fed mice. Moreover, HFD-induced adipocyte size enlargement and activation of lipolysis markers such as phosphorylated (p)-hormone-sensitive lipase (HSL) 565, p-HSL 660, and perilipin were inhibited in BA-5-treated mice. Notably, HFD-induced anxiety- and depression-like behaviors significantly improved in the BA-5 treated group through enhanced anti-inflammatory responses in the hippocampus. SIGNIFICANCE: This study provides new insights into clinical therapeutic strategies of barbituric acid derivatives for HFD-induced NAFLD and associated mood disturbances. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Suk, Fat-Moon AU - Suk FM AD - Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. FAU - Hsu, Fang-Yu AU - Hsu FY AD - School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Shuang-Ho Campus, New Taipei City 23561, Taiwan. FAU - Hsu, Ming-Hua AU - Hsu MH AD - Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan. FAU - Chiu, Wan-Chun AU - Chiu WC AD - School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan; Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan; Department of Nutrition, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan. FAU - Fang, Cheng-Chieh AU - Fang CC AD - School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Shuang-Ho Campus, New Taipei City 23561, Taiwan. FAU - Chen, Tzu-Lang AU - Chen TL AD - Department of Medical Education, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan. FAU - Liao, Yi-Jen AU - Liao YJ AD - School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Shuang-Ho Campus, New Taipei City 23561, Taiwan; TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: yjliao@tmu.edu.tw. LA - eng PT - Journal Article DEP - 20231206 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - WQ92Y2793G (barbituric acid) SB - IM MH - Male MH - Animals MH - Mice MH - *Non-alcoholic Fatty Liver Disease/drug therapy/etiology/metabolism MH - Mice, Inbred C57BL MH - Liver/metabolism MH - Diet, High-Fat/adverse effects OTO - NOTNLM OT - Barbituric acid derivative OT - Depression OT - High-fat diet OT - Nonalcoholic fatty liver disease COIS- Declaration of competing interest The authors declare that there are no conflicts of interest. EDAT- 2023/12/08 00:42 MHDA- 2023/12/25 06:42 CRDT- 2023/12/07 19:26 PHST- 2023/10/18 00:00 [received] PHST- 2023/11/21 00:00 [revised] PHST- 2023/11/30 00:00 [accepted] PHST- 2023/12/25 06:42 [medline] PHST- 2023/12/08 00:42 [pubmed] PHST- 2023/12/07 19:26 [entrez] AID - S0024-3205(23)00962-1 [pii] AID - 10.1016/j.lfs.2023.122327 [doi] PST - ppublish SO - Life Sci. 2024 Jan 1;336:122327. doi: 10.1016/j.lfs.2023.122327. Epub 2023 Dec 6.