title: Activation of farnesoid X receptor promotes triglycerides lowering by suppressing phospholipase A2 G12B expression.
abstract: As a novel mediator of hepatic very low-density lipoproteins (VLDL) secretion, phospholipase A2 G12B (PLA2G12B) is transcriptionally regulated by hepatocyte nuclear factor-4 alpha (HNF-4α). Farnesoid X receptor (FXR) plays a critical role in maintaining bile acids and triglycerides (TG) homeostasis. Here we report that FXR regulates serum TG level in part through PLA2G12B. Activation of FXR by chenodeoxycholic acid (CDCA) or GW4064 significantly decreased PLA2G12B expression in HepG2 cells. PLA2G12B expression was transcriptionally repressed due to an FXR-mediated up-regulation of small heterodimer partner (SHP) which functionally suppresses HNF-4α activity. We found that hepatic PLA2G12B expression was suppressed and serum TG level reduced in high fat diet mice treated with CDCA. Concurrently, CDCA treatment lowered hepatic VLDL-TG secretion. Our data demonstrate that activation of FXR promotes TG lowering, not only by decreasing de novo lipogenesis but also reducing hepatic secretion of TG-rich VLDL particles in part through suppressing PLA2G12B expression.
authors.affiliation: Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
authors.forename: Qingli
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
authors.forename: Xuekun
authors.initials: X
authors.lastname: Fu
authors.affiliation: Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
authors.forename: Renzhong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, Guangdong, China.
authors.forename: Caijun
authors.initials: C
authors.lastname: Sun
authors.affiliation: Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
authors.forename: Haobo
authors.initials: H
authors.lastname: Pan
authors.affiliation: NeuMed Pharmaceuticals Limited, Shatin, N. T., Hong Kong, China.
authors.forename: Chi-Wai
authors.initials: CW
authors.lastname: Wong
authors.affiliation: Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China. Electronic address: min.guan@siat.ac.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Guan
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D059305:Diet, High-Fat; D005786:Gene Expression Regulation / Q000187:drug effects; D054509:Group X Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006949:Hyperlipidemias / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D054509:Group X Phospholipases A2; D007555:Isoxazoles; D008024:Ligands; D008079:Lipoproteins, VLDL; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C000624540:PLA2G12B protein, human; C000624541:PLA2G12B protein, mouse; C412815:GW 4064
keywords: Farnesoid X receptor; Phospholipase A2 G12B; Triglyceride; Very low-density lipoprotein