Research Article Details
| Article ID: | A13185 |
| PMID: | 30096384 |
| Source: | Life Sci |
| Title: | Gut inflammation exacerbates hepatic injury in the high-fat diet induced NAFLD mouse: Attention to the gut-vascular barrier dysfunction. |
| Abstract: | AIMS: Gut inflammation has been put forward to be associated with hepatic injury in the clinical practice. The dismantled intestinal barrier was highly concerned, however, largely unknown about the role of gut-vascular barrier (GVB) in this process. This study aimed to investigate if inflamed gut directly contributes to the progression of non-alcoholic steatohepatitis (NASH), especially attention to the GVB dysfunction. MAIN METHODS: Male C57bl/6 mice were fed with a high-fat diet (HFD) and 1% DSS for 12 weeks. The colonic inflammatory injury as well as hepatic injury were evaluated. The GVB function was assessed via measuring the permeability to fluorescently-labeled dextran (70 kDa) and the expression of plasmalemma vesicle-associated protein-1 (PV1). Furthermore, the plasma endotoxin level and hepatic TLR4/TLR9 mRNA expression were detected. KEY FINDINGS: There were evident colitis in DSS-exposed mice, which trend to be more apparent in HFD ones. The HFD + DSS mice exhibited more serious hepatic steatosis, inflammation and fibrosis than HFD groups. The downregulated tight junction protein in HFD + DSS mice indicated loss of epithelial barrier. The GVB disruption were also confirmed with increased permeability to macromolecules and high expression of endothelial PV1 in HFD + DSS mice. Accordingly, potentially elevated plasma endotoxin levels and markedly increased TLR4/TLR9 mRNA expression were demonstrated in HFD + DSS mice rather than HFD groups. SIGNIFICANCE: Gut inflammation exacerbates liver injury and fibrosis in HFD mice, which may contribute to the development of NASH. Beyond the damaged intestinal epithelial barrier, GVB disruption with bacterial translocation into may play a key role in the pathogenesis of NASH. |
| DOI: | 10.1016/j.lfs.2018.08.017 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| 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 | |
|---|---|---|---|---|---|---|---|
| T09 | Toll-like receptor 4 | TLR4 | antagonist | Membrane receptor | O00206 | TLR4_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D010 | Amoxicillin | Chemical drug | DB01060 | -- | -- | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |