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1.
Exp Mol Med ; 55(7): 1437-1450, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37394591

RESUMO

Macrophages are immune cells crucial for host defense and homeostasis maintenance, and their dysregulation is involved in multiple pathological conditions, such as liver fibrosis. The transcriptional regulation in macrophage is indispensable for fine-tuning of macrophage functions, but the details have not been fully elucidated. Prolyl endopeptidase (PREP) is a dipeptidyl peptidase with both proteolytic and non-proteolytic functions. In this study, we found that Prep knockout significantly contributed to transcriptomic alterations in quiescent and M1/M2-polarized bone marrow-derived macrophages (BMDMs), as well as aggravated fibrosis in an experimental nonalcoholic steatohepatitis (NASH) model. Mechanistically, PREP predominantly localized to the macrophage nuclei and functioned as a transcriptional coregulator. Using CUT&Tag and co-immunoprecipitation, we found that PREP was mainly distributed in active cis-regulatory genomic regions and physically interacted with the transcription factor PU.1. Among PREP-regulated downstream genes, genes encoding profibrotic cathepsin B and D were overexpressed in BMDMs and fibrotic liver tissue. Our results indicate that PREP in macrophages functions as a transcriptional coregulator that finely tunes macrophage functions, and plays a protective role against liver fibrosis pathogenesis.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Prolil Oligopeptidases , Animais , Camundongos , Macrófagos , Fibrose , Hepatopatia Gordurosa não Alcoólica/patologia , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL
2.
Ann Transl Med ; 8(5): 218, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32309365

RESUMO

BACKGROUND: Prolyl endopeptidase (PREP) is a serine endopeptidase that regulates inflammatory responses. PREP inhibitors can reduce hepatocyte lipid accumulation and may participate in the progression of nonalcoholic fatty liver disease (NAFLD). We investigated whether disruption of PREP regulates hepatic steatosis and inflammation in mice with NAFLD. METHODS: Wild-type and PREP gene disrupted mice were randomly divided into low-fat diet wild-type (LFD-WT), high-fat diet wild-type (HFD-WT), low-fat diet PREP disruption (LFD-PREPgt), and high-fat diet PREP disruption (HFD-PREPgt) groups. Animals were euthanized at the endpoint of 32 weeks. The NAFLD activity score and number of inflammatory cells were determined by hematoxylin-eosin staining and immunohistochemical staining of liver tissue. The expression levels of inflammation- and lipid metabolism-associated genes in the liver and serum were detected by quantitative reverse transcription PCR, mass spectrometry, or enzyme-linked immunosorbent assay. RESULTS: The body weight and epididymal fat tissue index of the HFD-PREPgt mice were significantly decreased compared with that of the HFD-WT mice. Moreover, the NAFLD activity score and liver function were attenuated in the HFD-PREPgt mice. Fat accumulation and the level of expression of mRNAs associated with lipid metabolism and proinflammatory responses were improved in the HFD-PREPgt mice. The number of CD68-positive cells in liver tissue and the serum levels of inflammation-associated factors were significantly decreased in the HFD-PREPgt mice compared with those in the HFD-WT mice. Further mechanistic investigations indicated that the protective effect of PREP disruption on liver inflammation was associated with the suppressed production of matrix metalloproteinases (MMPs) and proline-glycine-proline (PGP) and the inhibition of neutrophil infiltration. CONCLUSIONS: Loss of PREP lowers the severity of hepatic steatosis and inflammatory responses in a high-fat diet-induced nonalcoholic steatohepatitis model. PREP inhibition may protect against NAFLD.

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