Demethylenetetrahydroberberine alleviates nonalcoholic fatty liver disease by inhibiting the NLRP3 inflammasome and oxidative stress in mice. 2021

Yuanqiang Zhang, and Jing Wen, and Dongqing Liu, and Zhen Qiu, and Qianqian Zhu, and Ruiyan Li, and Yubin Zhang
State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing, China.

OBJECTIVE Demethylenetetrahydroberberine (DMTHB) is a novel derivative of berberine and demethyleneberberine. This research explored the pharmacological effects and molecular mechanisms of DMTHB on nonalcoholic fatty liver disease (NAFLD). METHODS C57BL/6 mice were induced by a methionine- and choline- deficient (MCD) diet and L02 cells were induced by palmitic acid to establish NAFLD animal and cell models. qPCR and western blotting were used to detect the expression of genes and proteins associated with pharmacological mechanism. A biotin-labeled DMTHB pulldown assay was used to further clarify the pharmacological targets. RESULTS Our results indicated that DMTHB significantly alleviates NAFLD in mice. Biochemical assays showed that serum alanine aminotransferase, aspartate aminotransferase and hepatic lipids were significantly decreased in MCD-induced NAFLD mice orally administered of DMTHB (50 mg/kg or 150 mg/kg body weight daily) for 30 d. qPCR and ELISA analysis demonstrated that DMTHB reduced the expression of serum proinflammatory cytokines, such as TNF-α, IL-1β and IL-6. Moreover, pull-down assays and compound-centric chemical proteomics illustrated that DMTHB inhibited NOD-like receptor protein 3 (NLRP3) inflammasome signaling. In addition, DMTHB also attenuated oxidative stress and endoplasmic reticulum stress by downregulation CYP2E-1 and ATF-4 expression. Moreover, DMTHB treatment ameliorated the liver fibrosis in MCD-induced NAFLD mice by suppressing the expression of TGF-β1, α-SMA and collagen 1A1. CONCLUSIONS DMTHB targeted the NLRP3 inflammasome to suppress inflammation and inhibited CYP2E1 to reduce oxidative stress and ER stress. Consequently, DMTHB may have therapeutic benefits in the treatment of NAFLD in the clinic.

UI MeSH Term Description Entries
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071199 NLR Family, Pyrin Domain-Containing 3 Protein An NLR protein that contains an N-terminal PYRIN DOMAIN and ATP-binding site and 9 C-terminal LEUCINE-rich repeats; it is expressed primarily by MACROPHAGES. It is a core component of the INFLAMMASOME and directs its assembly in response to pathogen infection and damage-associated stimuli. Mutations in the NLRP3 gene are associated with FAMILIAL COLD AUTOINFLAMMATORY SYNDROME. Cold Autoinflammatory Syndrome 1 Protein,NACHT, LRR and PYD Domains-Containing Protein 3,NLRP3 Protein,NACHT, LRR and PYD Domains Containing Protein 3,NLR Family, Pyrin Domain Containing 3 Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001599 Berberine An alkaloid from Hydrastis canadensis L., Berberidaceae. It is also found in many other plants. It is relatively toxic parenterally, but has been used orally for various parasitic and fungal infections and as antidiarrheal. Umbellatine
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058847 Inflammasomes Multiprotein complexes that mediate the activation of CASPASE-1. Dysregulation of inflammasomes has also been linked to a number of autoinflammatory and autoimmune disorders. Inflammasome,Pyroptosome,Pyroptosomes
D018384 Oxidative Stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). Anti-oxidative Stress,Antioxidative Stress,DNA Oxidative Damage,Nitro-Oxidative Stress,Oxidative Cleavage,Oxidative DNA Damage,Oxidative Damage,Oxidative Injury,Oxidative Nitrative Stress,Oxidative Stress Injury,Oxidative and Nitrosative Stress,Stress, Oxidative,Anti oxidative Stress,Anti-oxidative Stresses,Antioxidative Stresses,Cleavage, Oxidative,DNA Damage, Oxidative,DNA Oxidative Damages,Damage, DNA Oxidative,Damage, Oxidative,Damage, Oxidative DNA,Injury, Oxidative,Injury, Oxidative Stress,Nitrative Stress, Oxidative,Nitro Oxidative Stress,Nitro-Oxidative Stresses,Oxidative Cleavages,Oxidative DNA Damages,Oxidative Damage, DNA,Oxidative Damages,Oxidative Injuries,Oxidative Nitrative Stresses,Oxidative Stress Injuries,Oxidative Stresses,Stress Injury, Oxidative,Stress, Anti-oxidative,Stress, Antioxidative,Stress, Nitro-Oxidative,Stress, Oxidative Nitrative,Stresses, Nitro-Oxidative
D065626 Non-alcoholic Fatty Liver Disease Fatty liver finding without excessive ALCOHOL CONSUMPTION. Fatty Liver, Nonalcoholic,NAFLD,Nonalcoholic Fatty Liver Disease,Nonalcoholic Steatohepatitis,Fatty Livers, Nonalcoholic,Liver, Nonalcoholic Fatty,Livers, Nonalcoholic Fatty,Non alcoholic Fatty Liver Disease,Nonalcoholic Fatty Liver,Nonalcoholic Fatty Livers,Nonalcoholic Steatohepatitides,Steatohepatitides, Nonalcoholic,Steatohepatitis, Nonalcoholic

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