Jingjing Duan1, Zhuo Wang2, Ran Duan1, Chenxinhui Yang1, Ruolin Zhao1, Qi Feng1, Yuanyuan Qin1, Jingwei Jiang1, Shouyong Gu3, Kaiyan Lv1, Libo Zhang1, Bixia He1, Lutz Birnbaumer4,5, Song Yang6, Zhen Chen1, Yong Yang1. 1. Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. 2. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. 3. Province Geriatric Hospital, Nanjing, China. 4. Institute of Biomedical Research (BIOMED), Catholic University of Argentina, Buenos Aires, Argentina. 5. Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA. 6. Center of Hepatology, Beijing Ditan Hospital of Capital Medical University, Beijing, China.
Abstract
BACKGROUND AND AIMS: Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity. APPROACH AND RESULTS: In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β-oxidation of fatty acids and to minimize lipid accumulation by up-regulating peroxisome proliferator-activated receptor coactivator-1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models. CONCLUSIONS: Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.
BACKGROUND AND AIMS: Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity. APPROACH AND RESULTS: In this study, we showed that compared with healthy controls, hepatic ACSL4 levels in patients with NAFLD were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β-oxidation of fatty acids and to minimize lipid accumulation by up-regulating peroxisome proliferator-activated receptor coactivator-1 alpha. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, and low dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models. CONCLUSIONS: Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.
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