Abstract
Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in patients with alcohol-associated liver disease (ALD), but how LSEC alteration contributes to the pathogenesis of ALD remains unclear. Here, we found that the hepatic level of thioredoxin interacting protein (TXNIP) was up-regulated in ALD patients and ethanol diet-fed mice with high expression in LSECs. Notably, endothelial cell-specific Txnip deficiency in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma (HCC) development. Deletion of Txnip in LSECs led to sinusoidal capillarization, down-regulation of endothelial nitric oxide synthase (eNOS) level and nitric oxide (NO) production, and increased release of pro-inflammatory cytokines and adhesion molecules. Mechanistically, TXNIP interacted with transforming growth factor β- activated kinase 1 (TAK1) and subsequently suppressed TAK1/c-Jun N-terminal kinase (JNK) pathway. Inhibition of TAK1 activation restored the effect of Txnip deficiency on LSECs, thereby blocking ethanol-induced liver injury and inflammation. Overall, TXNIP in LSECs protects against ALD progression through TAK1/JNK signaling and TXNIP targeting may be a potential therapeutic approach for ALD.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
List of abbreviations: ADH, alcohol dehydrogenase; ALD, alcohol-associated liver disease; ALDH2, aldehyde dehydrogenase 2; ALT, aspartate transaminase; AST, alanine transaminase; CYP2E1, cytochrome P450 family 2 subfamily E member 1; CCL4, C-C motif chemokine 4; COL1α1, collagen 1 α1; DEGs, differentially expressed genes; ECs, endothelial cells; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal- regulated kinase; ET-1, endothelin-1; HCC, hepatocellular carcinoma; HSCs, hepatic stellate cells; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; JNK, c-Jun N-terminal kinase; KCs, Kupffer cells; KEGG, Kyoto encyclopedia of genes and genomes; LPS, Lipopolysaccharide; LSECs, liver sinusoidal endothelial cells; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1; MCP-1, monocyte chemoattractant protein-1; NAFLD, nonalcoholic fatty liver disease; NO, nitric oxide; TAK1, transforming growth factor β- activated kinase 1; TGF-β, transforming growth factor-β; TIMP-1, tissue inhibitor of metalloproteinases-1; TNF-α, tumor necrosis factor-α; TXNIP, thioredoxin interacting protein; α-SMA, alpha-smooth muscle actin; VAP-1, vascular adhesion protein 1, VCAM-1, vascular cell adhesion protein 1; WT, wild-type.