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Although there are increasing publications and patent applications to lower blood cholesterol with small chemical molecules, limited effective drugs can be available in clinic. It is necessary to uncover new targets and drugs to alleviate high cholesterol. Esterase D (ESD) is abundant in liver and it remains unknown about its role in cholesterol metabolism. Here we reported that small chemical molecule fluorescigenic pyrazoline derivative 5 (FPD5), a new ESD\u00a0activator, could effectively reverse high blood cholesterol level and prevent fatty liver and arteriosclerosis in apoE<jats:sup>\u2212\/\u2212<\/jats:sup> mice fed the high\u2010fat diet. We also observed that FPD5 could reduce oxidized low density lipoprotein (oxLDL)\u2010induced formation of foam cells. To further investigate the mechanism of FPD5 action on blood cholesterol modulation, we found that ESD trigged by FPD5 was aggregated in lysosome and interacted with Jun activation domain binding protein 1 (JAB1). ESD served as a deacetylase to remove Thr89 acetylation of JAB1 and increased its activity; thus,\u00a0promoting the ATP\u2010binding cassette transporters A1 (ABCA1) to accelerate cholesterol efflux. Our findings demonstrate that FPD5 decreases blood cholesterol level to ameliorate NAFLD and arteriosclerosis through ESD\/JAB1\/ABCA1 pathway, and ESD functions as a novel nonclassical deacetylase that hydrolyzes serine\/threonine acetyl group. Our findings not only highlight that FPD5 may be a pioneer drug for alleviating blood cholesterol\u00a0but also indicate that ESD is a potential drug target that promotes cholesterol metabolism.<\/jats:p>","DOI":"10.1002\/jcp.30196","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T07:28:42Z","timestamp":1607412522000},"page":"4750-4763","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A new activator of esterase D decreases blood cholesterol level through ESD\/JAB1\/ABCA1 pathway"],"prefix":"10.1002","volume":"236","author":[{"given":"Xinpeng","family":"Chen","sequence":"first","affiliation":[{"name":"Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science Shandong University  Qingdao P.R. 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