title: TNF-α decreases lipoprotein lipase activity in 3T3-L1 adipocytes by up-regulation of angiopoietin-like protein 4.
abstract: Lipoprotein lipase (LPL) hydrolyzes lipids in plasma lipoproteins so that the fatty acids can be taken up and used by cells. The activity of LPL changes rapidly in response to changes in nutrition, physical activity and other conditions. Angiopoietin-like protein 4 (ANGPTL4) is an important controller of LPL activity. Both LPL and ANGPTL4 are produced and secreted by adipocytes. When the transcription blocker Actinomycin D was added to cultures of 3T3-L1 adipocytes, LPL activity in the medium increased several-fold. LPL mRNA decreased moderately during 5h, while ANGPTL4 mRNA and protein declined rapidly, explaining that LPL activity was increased. TNF-α is known to reduce LPL activity in adipose tissue. We have shown that TNF-α increased ANGPTL4 both at the mRNA and protein level. Expression of ANGPTL4 is known to be under control of Foxo1. Use of the Foxo1-specific inhibitor AS1842856, or knockdown of ANGPTL4 by RNAi, resulted in increased LPL activity in the medium. Both with ActD and with the Foxo1 inhibitor the cells became unresponsive to TNF-α. This study shows that TNF-α, by a Foxo1 dependent pathway, increases the transcription of ANGPTL4 which is secreted by the cells and causes inactivation of LPL.
authors.affiliation: Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Makoveichuk
authors.affiliation: Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Evelina
authors.initials: E
authors.lastname: Vorrsjö
authors.affiliation: Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Olivecrona
authors.affiliation: Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden. Electronic address: gunilla.olivecrona@umu.se.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D003609:Dactinomycin / Q000008:administration & dosage; D000071161:Forkhead Box Protein O1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D015363:Quinolones / Q000008:administration & dosage; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D015363:Quinolones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D008071:Lipoprotein Lipase
keywords: 3T3-L1 adipocytes; Actinomycin D; Angiopoietin-like protein 4; Foxo1 inhibitor; Lipoprotein lipase; TNF-α