title: Down-regulated expression of PPARalpha target genes, reduced fatty acid oxidation and altered fatty acid composition in the liver of mice transgenic for hTNFalpha.
abstract: The present study investigated the hepatic regulation of fatty acid metabolism in hTNFalpha transgenic mice. Reduced hepatic mRNA levels and activities of carnitine palmitoyltransferase-II (CPT-II) and mitochondrial HMG-CoA synthase were observed, accompanied by decreased fatty acid oxidation, fatty acyl-CoA oxidase and fatty acid synthase (FAS) activities and down-regulated gene expression of mitochondrial acetyl-CoA carboxylase 2 (ACC2). The mRNA levels of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARdelta were reduced. The hepatic fatty acid composition was altered, with increased amounts of saturated and polyunsaturated fatty acids. The relative amounts of Delta(9) desaturated fatty acids were decreased, as was Delta(9)desaturase mRNA. The CPT-I mRNA level remained unchanged. The PPARalpha targeted genes CPT-II and HMG-CoA synthase are potential regulators of mitochondrial fatty acid oxidation and ketogenesis in hTNFalpha transgenic mice, and the increased propionyl-CoA level found is a possible inhibitor of these processes. Reduced mitochondrial and peroxisomal fatty acid oxidation may explain the increased hepatic triglyceride level induced by TNFalpha. This is not due to de novo fatty acid synthesis as both FAS activity and gene expression of ACC2 were reduced.
authors.affiliation: Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Heidi
authors.initials: H
authors.lastname: Glosli
authors.forename: Oddrun Anita
authors.initials: OA
authors.lastname: Gudbrandsen
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Mullen
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Therese H
authors.initials: TH
authors.lastname: Røst
authors.forename: Hege
authors.initials: H
authors.lastname: Wergedahl
authors.forename: Hans
authors.initials: H
authors.lastname: Prydz
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
mesh_terms: D000818:Animals; D003066:Coenzyme A Ligases / Q000032:analysis; D015536:Down-Regulation; D044943:Fatty Acid Desaturases / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000032:analysis; D005227:Fatty Acids / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000032:analysis / Q000097:blood / Q000378:metabolism; D005260:Female; D006904:Hydroxymethylglutaryl-CoA Synthase; D007651:Keto Acids / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D013230:Stearoyl-CoA Desaturase; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D007651:Keto Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase; D064429:Fatty Acid Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase; D003066:Coenzyme A Ligases