title: Hypoxia-inducible lipid droplet-associated (HILPDA) is a novel peroxisome proliferator-activated receptor (PPAR) target involved in hepatic triglyceride secretion.
abstract: Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a novel PPAR target gene and demonstrate its involvement in hepatic lipid metabolism. Microarray analysis revealed that Hilpda is one of the most highly induced genes by the PPARα agonist Wy14643 in mouse precision cut liver slices. Induction of Hilpda mRNA by Wy14643 was confirmed in mouse and human hepatocytes. Oral dosing with Wy14643 similarly induced Hilpda mRNA levels in livers of wild-type mice but not Ppara(-/-) mice. Transactivation studies and chromatin immunoprecipitation showed that Hilpda is a direct PPARα target gene via a conserved PPAR response element located 1200 base pairs upstream of the transcription start site. Hepatic overexpression of HILPDA in mice via adeno-associated virus led to a 4-fold increase in liver triglyceride storage, without any changes in key genes involved in de novo lipogenesis, β-oxidation, or lipolysis. Moreover, intracellular lipase activity was not affected by HILPDA overexpression. Strikingly, HILPDA overexpression significantly impaired hepatic triglyceride secretion. Taken together, our data uncover HILPDA as a novel PPAR target that raises hepatic triglyceride storage via regulation of triglyceride secretion.
authors.affiliation: From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Frits
authors.initials: F
authors.lastname: Mattijssen
authors.affiliation: From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Georgiadi
authors.affiliation: From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
authors.forename: Tresty
authors.initials: T
authors.lastname: Andasarie
authors.affiliation: the RIKILT-Institute of Food Safety, Wageningen University and Research Centre, 6700AE Wageningen, The Netherlands.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szalowska
authors.affiliation: the Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH), and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Zota
authors.affiliation: the Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH), and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Krones-Herzig
authors.affiliation: the Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heier
authors.affiliation: the Cytokine Receptor Laboratory, Nuclear Receptor Signaling Unit, Department of Medical Protein Research, Flanders Institute for Biotechnology, University of Ghent, Albert Baertsoenkaai 3, B-9000 Gent, Belgium, and.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Ratman
authors.affiliation: the Cytokine Receptor Laboratory, Nuclear Receptor Signaling Unit, Department of Medical Protein Research, Flanders Institute for Biotechnology, University of Ghent, Albert Baertsoenkaai 3, B-9000 Gent, Belgium, and.
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.affiliation: the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.affiliation: the Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: the Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH), and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.affiliation: From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands, the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853 sander.kersten@wur.nl.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements / Q000502:physiology; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; C405620:HILPDA protein, human; D009363:Neoplasm Proteins; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D014280:Triglycerides; C006253:pirinixic acid
keywords: Hig2; Lipid Droplets; Lipoprotein Secretion; Liver Metabolism; Liver Slices; Nuclear Receptor; PPRE; Peroxisome Proliferator-activated Receptor (PPAR); Steatosis; VLDL