title: Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress.
abstract: Non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level globally, which is recognized to form non-alcoholic steatohepatitis (NASH) by the "two-hit" model, including oxidative stress and inflammation. AMP-activated protein kinase (AMPK) has long been regarded as a key regulator of energy metabolism, which is recognized as a critical target for NAFLD treatment. Here we introduce a natural product, demethyleneberberine (DMB), which potentially ameliorated NAFLD by activating AMPK pathways. Our study showed that the intraperitoneal injection of DMB (20 or 40 mg/kg body weight) decreased hepatic lipid accumulation in methionine and choline deficient (MCD) high-fat diet feeding mice and db/db mice. The further investigation demonstrated that DMB activated AMPK by increasing its phosphorylation in vitro and in vivo. Accompanied with AMPK activation, the expression of lipogenic genes were significantly reduced while genes responsible for the fatty acid β-oxidation were restored in DMB-treated NAFLD mice. In addition, the remarkable oxidative damage and inflammation induced by NAFLD were both attenuated by DMB treatment, which is reflected by decreased lipid oxidative product, malonaldehyde (MDA) and inflammatory factors, tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). Based on all above, DMB could serve as a novel AMPK activator for treating NAFLD and preventing the pathologic progression from NAFLD to NASH by inhibiting the oxidative stress and inflammation.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China; Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yinhang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yongchen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Toxicology, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing 210009, China.
authors.forename: Xie
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: ybzhang@cpu.edu.cn.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001599:Berberine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D001599:Berberine; C477155:demethyleneberberine; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Demethyeneberberine; Hepatosteatosis; Inflammation; Non-alcoholic liver disease; Oxidative stress