title: Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression.
abstract: Adaptation to hypoxia involves hypoxia-inducible transcription factors (HIFs) and requires reprogramming of cellular metabolism that is essential during both physiological and pathological processes. In contrast to the established role of HIF-1 in glucose metabolism, the involvement of HIFs and the molecular mechanisms concerning the effects of hypoxia on lipid metabolism are poorly characterized. Here, we report that exposure of human cells to hypoxia causes accumulation of triglycerides and lipid droplets. This is accompanied by induction of lipin 1, a phosphatidate phosphatase isoform that catalyzes the penultimate step in triglyceride biosynthesis, whereas lipin 2 remains unaffected. Hypoxic upregulation of lipin 1 expression involves predominantly HIF-1, which binds to a single distal hypoxia-responsive element in the lipin 1 gene promoter and causes its activation under low oxygen conditions. Accumulation of hypoxic triglycerides or lipid droplets can be blocked by siRNA-mediated silencing of lipin 1 expression or kaempferol-mediated inhibition of HIF-1. We conclude that direct control of lipin 1 transcription by HIF-1 is an important regulatory feature of lipid metabolism and its adaptation to hypoxia.
authors.affiliation: Laboratory of Biochemistry, Medical School, University of Thessaly, BIOPOLIS, Larissa 41110,  Greece.
authors.forename: Ilias
authors.initials: I
authors.lastname: Mylonis
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sembongi
authors.forename: Christina
authors.initials: C
authors.lastname: Befani
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Liakos
authors.forename: Symeon
authors.initials: S
authors.lastname: Siniossoglou
authors.forename: George
authors.initials: G
authors.lastname: Simos
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D014280:Triglycerides / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051793:Hypoxia-Inducible Factor 1; D014280:Triglycerides; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase