Research Article Details
| Article ID: | A00696 |
| PMID: | 34999396 |
| Source: | Int Immunopharmacol |
| Title: | Liensinine alleviates high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) through suppressing oxidative stress and inflammation via regulating TAK1/AMPK signaling. |
| Abstract: | Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases without effective pharmacological intervention. Liensinine (LIEN), a plant-derived isoquinoline alkaloid, exerts key roles in regulating various cellular processes. However, its potential on NAFLD progression has not been reported. In the study, we attempted to explore the regulatory effects of LIEN on fatty liver, and the underlying molecular mechanisms. Our in vitro experiments showed that LIEN treatments significantly reduced the lipid deposition in palmitate acid (PA)-treated cells by improving AMP-activated protein kinase (AMPK) activation. Additionally, excessive reactive oxygen species (ROS) generation was also strongly down-regulated by LIEN in cells upon PA stimulation through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. Moreover, PA-triggered inflammatory response was markedly restrained by LIEN via the blockage of TGF-β-activating kinase 1/nuclear factor-κB (TAK1/NF-κB) signaling. Intriguingly, we further found that LIEN-prohibited ROS production, lipid disorder and inflammation were largely dependent on AMPK activation through repressing TAK1. Consistently, our in vivo experiments confirmed that LIEN treatments efficiently improved the metabolic disorder, insulin resistance, dyslipidemia in high fat diet (HFD)-fed mice. Furthermore, HFD-triggered oxidative stress and inflammation in liver were greatly meliorated by LIEN administration by mediating Nrf2 and TAK1 signaling pathways, respectively. Collectively, all these findings demonstrated that LIEN exerted anti-dyslipidemia, anti-oxidant and anti-inflammatory effects to alleviate NAFLD progression mainly through modulating TAK1/AMPK signaling, and thus could be considered as a promising therapeutic strategy. |
| DOI: | 10.1016/j.intimp.2021.108306 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T43 | TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 | TAB1 | inhibitor | Kinase | Q15750 | TAB1_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |