Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells.

Autor: Yao JM; Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China., Ying HZ; Zhejiang Provincial Laboratory of Experimental Animal's & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, China., Zhang HH; Zhejiang Provincial Laboratory of Experimental Animal's & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, China., Qiu FS; Zhejiang Provincial Laboratory of Experimental Animal's & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, China; Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310018, China; Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China., Wu JQ; Clinical Laboratory, Jinhua Municipal Central Hospital Medical Group, Jinhua, 321000, China., Yu CH; Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310018, China; Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China; Institute of Rheumatology and Immunology, Zhejiang Provincial People's Hospital (Hangzhou Medical College), Hangzhou, 310014, China. Electronic address: yuchenhuan2002@163.com.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2023 Feb 01; Vol. 195, pp. 58-73. Date of Electronic Publication: 2022 Dec 24.
DOI: 10.1016/j.freeradbiomed.2022.12.085
Abstrakt: Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 μg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this work.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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