Research Article Details

Article ID: A25570
PMID: 21703208
Source: J Hepatol
Title: DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH.
Abstract: BACKGROUND & AIMS: Intestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextran sulfate sodium (DSS) is a colitis model in mice characterized by damage of the intestinal barrier. This study was designed to investigate if application of DSS aggravates experimental NASH. METHODS: Male C57bl/6 mice were allocated into four experimental groups receiving either (I) standard chow (SC), (II) a high fat (HF) diet, (III) SC+DSS (1% in the drinking water), and (IV) HF+DSS for 12 weeks. RESULTS: DSS treatment caused inflammation and proinflammatory gene expression (IL-1β, IL-17, TNF) in the colon. Expression of colonic antimicrobial peptide Cramp was significantly induced in SC+DSS mice, whereas expression was blocked in the HF+DSS group. Endotoxin levels were elevated in SC+DSS and HF mice but further augmented in the HF+DSS group. In line with this, increased hepatic TLR4 and TLR9 mRNA levels were detected in HF+DSS mice. The histological analysis revealed hepatic steatosis in both HF groups. Hepatic inflammation was more severe in HF+DSS mice, reflected by histology and analysis of proinflammatory gene expression (TNF and MCP-1). HF+DSS mice showed increased hepatic fibrosis by sirius red staining, hepatic collagen I expression, and α-SMA positive cells accompanied by higher p47(phox), TIMP-1, TGF-β, Pai-1, and α-SMA mRNA expression. CONCLUSIONS: Induction of an intestinal inflammation in experimental NASH promotes LPS translocation, hepatic inflammation, and fibrogenesis probably due to inhibition of intestinal antimicrobial peptides. These findings underscore the pathophysiological role of the gut-liver axis in the progression of NASH.
DOI: 10.1016/j.jhep.2011.02.035

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
T07 Bile acid receptor NR1H4 agonist Nuclear hormone receptor Q96RI1 NR1H4_HUMAN Details
T08 Tumor necrosis factor TNF inhibitor Cytokine P01375 TNFA_HUMAN Details
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

Diseases ID DO ID Disease Name Definition Class

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D010 Amoxicillin Chemical drug DB01060 -- -- Under clinical trials Details
D080 Citrulline Chemical drug DB00155 -- -- 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