Research Article Details
| Article ID: | A08276 |
| PMID: | 32171530 |
| Source: | Biochem Biophys Res Commun |
| Title: | Liraglutide ameliorates obesity-related nonalcoholic fatty liver disease by regulating Sestrin2-mediated Nrf2/HO-1 pathway. |
| Abstract: | Liraglutide, a glucagon-like peptide 1 (GLP-1) analogue, could reverse NAFLD-induced liver damage by improving metabolic profiles, but the exact molecular mechanism has not been elucidated. Sestrin2 is a novel antioxidant protein, essential for regulating metabolic homeostasis. However, whether sestrin2-mediated redox balance participated in the protective effects of liraglutide against NAFLD is still elusive. The aim of the study was to determine whether liraglutide could ameliorate NAFLD by increasing Sestrin2-mediated signaling in obese mice. Following a normal diet or high fat diet (HFD) for 8 weeks, male C57BL/6 mice were treated with or without liraglutide for 4 weeks. Function and histopathology of liver were conducted to evaluate liver injury. Sestrin2-related AMPK and Nrf2/HO-1 pathway were examined. Antioxidative and inflammatory genes and were determined. HFD mice displayed significantly increased body weight, fat mass, lipids levels and impaired glucose homeostasis with reduced glucose tolerance and insulin sensitivity. Metabolic profiles, hepatic injury, and hepatic lipid accumulation from HFD mice were improved by liraglutide treatment. Liraglutide enhanced Sestrin2, phosphorylated AMPK, Nrf2, and HO-1 protein levels. Additionally, Liraglutide treatment increased mRNA levels of Sestrin2, Nrf2, HO-1 and down-stream genes catalase, GCLM and NQO1, but reduced malondialdehyde and TNF-α levels. Our findings indicated that liraglutide ameliorated obesity-related NAFLD through upregulating Sestrin2-mediated Nrf2/HO-1 pathway. |
| DOI: | 10.1016/j.bbrc.2020.03.032 |
| 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 |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | 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 |
| T06 | Glucagon-like peptide 1 receptor | GLP1R | agonist | GPCR | P43220 | GLP1R_HUMAN | Details |
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D482 | Heme Oxygenase | Biological drug | -- | -- | -- | Under clinical trials | Details |
| D155 | Glucagon | Biological drug | DB00040 | GCGR agonist | Antidiabetic drug | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D207 | Liraglutide | Biological drug | DB06655 | GLP1R activator; GLP1R agonist; GCG receptor antagonist activity | Improve insulin resistance | Under clinical trials | Details |