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Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension.

ABSTRACT: Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2-/- mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2-/- mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.

SUBMITTER: Chen J

PROVIDER: S-EPMC7512007 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension.

Chen Jiegen J Argemi Josepmaria J Odena Gemma G Xu Ming-Jiang MJ Cai Yan Y Massey Veronica V Parrish Austin A Vadigepalli Rajanikanth R Altamirano Jose J Cabezas Joaquin J Gines Pere P Caballeria Juan J Snider Natasha N Sancho-Bru Pau P Akira Shizuo S Rusyn Ivan I Gao Bin B Bataller Ramon R

Scientific reports 20200923 1

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 exp ...[more]

PMID: 32968110

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Project description:Background and aimsDuring liver fibrosis, liver sinusoidal endothelial cells (LSECs) release angiocrine signals to recruit inflammatory cells into the liver. p300, a master regulator of gene transcription, is associated with pathological inflammatory response. Therefore, we examined how endothelial p300 regulates angiocrine signaling and inflammation related to portal hypertension and fibrogenesis.Approach and resultsCCl4 or partial inferior vena cava ligation (pIVCL) was used to induce liver injury. Mice with LSEC-specific p300 deletion (p300LSECΔ/Δ ) or C-C motif chemokine ligand 2 (Ccl2) deficiency, nuclear factor kappa B (NFκB)-p50 knockout mice, and bromodomain containing 4 (BRD4) inhibitors in wild-type mice were used to investigate mechanisms of inflammation regulation. Leukocytes were analyzed by mass cytometry by time-of-flight. Epigenetic histone marks were modified by CRISPR endonuclease-deficient CRISPR-associated 9-fused with the Krüppel associated box domain (CRISPR-dCas9-KRAB)-mediated epigenome editing. Portal pressure and liver fibrosis were reduced in p300LSECΔ/Δ mice compared to p300fl/fl mice following liver injury. Accumulation of macrophages was also reduced in p300LSECΔ/Δ mouse livers. Ccl2 was the most up-regulated chemokine in injured LSECs, but its increase was abrogated in p300LSECΔ/Δ mice. While the macrophage accumulation was increased in NFκB-p50 knockout mice with enhanced NFκB activity, it was reduced in mice with LSEC-specific Ccl2 deficiency and mice treated with specific BRD4 inhibitors. In vitro, epigenome editing of CCL2 enhancer and promoter regions by CRISPR-dCas9-KRAB technology repressed TNFα-induced CCL2 transcription through H3K9 trimethylation. In contrast, TNFα activated CCL2 transcription by promoting p300 interaction with NFκB and BRD4, leading to histone H3 lysine 27 acetylation at CCL2 enhancer and promoter regions.ConclusionsIn summary, endothelial p300 interaction with NFκB and BRD4 increases CCL2 expression, leading to macrophage accumulation, portal hypertension, and liver fibrosis. Inhibition of p300 and its binding partners might serve as therapy in the treatment of liver diseases.

Project description:Liver disease is the third leading cause of death in patients with cystic fibrosis (CF), but features of patients with CF, severe liver disease, and portal hypertension have not been characterized fully.We performed a retrospective analysis of data from 561 patients with CF (63% male, 99% with pancreatic insufficiency), liver disease (hepatic parenchymal abnormalities consistent with cirrhosis, confirmed by imaging), and portal hypertension (esophageal varices, portosystemic collaterals, or splenomegaly), with no alternate causes of liver disease. All patients were enrolled in the Genetic Modifier Study of Severe CF Liver Disease at 76 international centers, from January 1999 through July 2013.Male patients were diagnosed with liver disease at a younger age than female patients (10 vs 11 y; P = .01). Splenomegaly was observed in 99% of patients and varices in 71%. Levels of liver enzymes were near normal in most patients. Thrombocytopenia affected 70% of patients and was more severe in patients with varices (88 × 10(9)/L vs 145 × 10(9)/L; P < .0001). Ninety-one patients received liver transplants (16%), at a median age of 13.9 years. Compared with patients who did not receive liver transplants, patients who received liver transplants had lower platelet counts (78 × 10(9)/L vs 113 × 10(9)/L; P < .0001), higher international normalized ratios (P < .0001), and lower levels of albumin (P = .0002). The aminotransferase to platelet ratio index (APRi) and fibrosis index based on 4 factor (FIB-4) values were higher than the diagnostic thresholds for CF liver disease in 96% and in 90% of patients, respectively. Patients who received liver transplants or who had varices had higher APRi and FIB-4 values than patients who did not.In patients with CF, severe liver disease develops early in childhood (approximately 10 years of age), and is more common in boys than in girls. Patients with varices and those who receive liver transplants have more abnormal platelet counts and APRi and FIB-4 scores.

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Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension.

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Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension.

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