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Reverse cholesterol transport (RCT) is a mechanism by which excess peripheral cholesterol is transported to the liver and further converted into bile acid for excretion from the body in feces, which contributes to reducing hyperlipidemia as well as cardiovascular disease. We previously found that the recombinant humanized IgG1 antibody promotes macrophages to engulf lipids and increases cholesterol efflux to high-density lipoprotein (HDL) through ATP-binding cassette sub-family A1 (ABCA1), one of the key proteins related to RCT. In the present study, we explored other RCT related proteins expression on hepatocytes, including scavenger receptor class B type I (SR-BI), apolipoprotein A-I (ApoA-I), and apolipoprotein A-II (ApoA-II), and its modulation mechanism involved. We confirmed that the recombinant humanized IgG1 antibody selectively activated ERK1\/2 to upregulate SR-BI, ApoA-I, and ApoA-II expression in mice liver and human hepatocellular carcinoma cell lines HepG2 cells. The rate-limiting enzymes of bile acid synthesis, including cholesterol 7\u03b1-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), exhibited a significant increase when treated with the recombinant humanized IgG1 antibody, as well as increased excretion of bile acids in feces. Besides, abolishment or mutation of peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1)\/RXR binding site on SR-BI promoter eliminated SR-BI reporter gene luciferase activity even in the presence of the recombinant humanized IgG1 antibody. Knock down the neonatal Fc receptor (FcRn) on hepatocytes impaired the effect of recombinant humanized IgG1 antibody on activation of ERK1\/2, as well as upregulation of SR-BI, ApoA-I, and ApoA-II expression. In conclusion, one of the mechanisms on the recombinant humanized IgG1 antibody attenuates hyperlipidemia in ApoE\u2212\/\u2212 mice model fed with high-fat-diet might be through reinforcement of liver RCT function in an FcRn-ERK1\/2-PPAR\u03b1 dependent manner.<\/jats:p>","DOI":"10.3390\/ijms232314607","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T09:50:52Z","timestamp":1669197052000},"page":"14607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1\/2-PPAR\u03b1 Pathway in Hepatocytes"],"prefix":"10.3390","volume":"23","author":[{"given":"Zhonghao","family":"Li","sequence":"first","affiliation":[{"name":"Key Lab for Shock and Microcirculation Research of Guangdong, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Lab for Shock and Microcirculation Research of Guangdong, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Lab for Shock and Microcirculation Research of Guangdong, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nrendo.2016.210","article-title":"Functional foods and dietary supplements for the management of dyslipidaemia","volume":"13","author":"Hunter","year":"2017","journal-title":"Nat. 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