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Demethylenetetrahydroberberine alleviates nonalcoholic fatty liver disease by inhibiting the NLRP3 inflammasome and oxidative stress in mice
- Source :
- Life Sciences. 281:119778
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Aims 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). Materials and 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. Key findings 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. Significance 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.
- Subjects :
- Male
0301 basic medicine
Berberine
Inflammasomes
Inflammation
Pharmacology
medicine.disease_cause
030226 pharmacology & pharmacy
General Biochemistry, Genetics and Molecular Biology
Proinflammatory cytokine
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Non-alcoholic Fatty Liver Disease
NLR Family, Pyrin Domain-Containing 3 Protein
Nonalcoholic fatty liver disease
medicine
Animals
Humans
General Pharmacology, Toxicology and Pharmaceutics
Chemistry
nutritional and metabolic diseases
Inflammasome
General Medicine
CYP2E1
medicine.disease
Mice, Inbred C57BL
Oxidative Stress
030104 developmental biology
Unfolded protein response
medicine.symptom
Oxidative stress
medicine.drug
Subjects
Details
- ISSN :
- 00243205
- Volume :
- 281
- Database :
- OpenAIRE
- Journal :
- Life Sciences
- Accession number :
- edsair.doi.dedup.....10c853afb78471ec241e1df732240a41