Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease

Peroxisome proliferator-activated receptor alpha (PPAR-a) is a crucial nuclear transcription regulator of lipid metabolism, which is closely associated with the initiation and development of nonalcoholic fatty liver disease (NAFLD). Because PPAR-a can directly decide the level of peroxisomal metabol...

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Published in:Analytical chemistry (Washington) 2021-07, Vol.93 (27), p.9609-9620
Main Authors: Zhou, Yongqing, Wu, Chuanchen, Wang, Xin, Li, Ping, Fan, Nannan, Zhang, Wei, Liu, Zhenzhen, Zhang, Wen, Tang, Bo
Format: Article
Language:English
Subjects:
Chemistry
Cyanides
Fatty liver
Fluorescence
Hydrogen peroxide
Lipid metabolism
Lipids
Liver
Liver diseases
Nitrification
Oxidation
Peroxisome proliferator-activated receptors
Peroxynitrite
Pioglitazone
Polarity
Target recognition
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Summary:Peroxisome proliferator-activated receptor alpha (PPAR-a) is a crucial nuclear transcription regulator of lipid metabolism, which is closely associated with the initiation and development of nonalcoholic fatty liver disease (NAFLD). Because PPAR-a can directly decide the level of peroxisomal metabolic enzymes, its changes might directly cause variations in peroxisomal polarity. Therefore, we developed a new two-photon fluorescence imaging probe, PX-P, in which the triphenylamine and cyanide moieties can real-time sense peroxisomal polarity changes. Using PX-P, we observed a prominent decrease in the peroxisomal polarity in the liver of mice with NAFLD for the first time. More importantly, we discovered that intracellular excessive peroxynitrite (ONOO–) and hydrogen peroxide (H2O2) underwent nitrification and oxidation, respectively, with various sites of PPAR-a. Interestingly, the key site of PPAR-a was nitrated by a low concentration of ONOO– rather than being oxidized by the high level of H2O2. These drastically reduced the activity of PPAR-a, accelerating the occurrence of NAFLD. Moreover, through activating PPARs with pioglitazone, peroxisomal polarity markedly increased compared with that of NAFLD. Altogether, our work presents a new approach for the early diagnosis of NAFLD and identifies potential therapeutic targets.
ISSN:0003-2700
1520-6882
DOI:10.1021/acs.analchem.1c01776