title: Peroxisome-proliferator-activated receptor-alpha (PPARalpha) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin.
abstract: The aim of the present study was to determine whether peroxisome-proliferator-activated receptor-alpha (PPARalpha) deficiency disrupts the normal regulation of triacylglycerol (TAG) accumulation, hepatic lipogenesis and glycogenesis by fatty acids and insulin using PPARalpha-null mice. In wild-type mice, hepatic TAG concentrations increased (P<0.01) with fasting (24 h), with substantial reversal after refeeding (6 h). Hepatic TAG levels in fed PPARalpha-null mice were 2.4-fold higher than in the wild-type (P<0.05), increased with fasting, but remained elevated after refeeding. PPARalpha deficiency also impaired hepatic glycogen repletion (P<0.001), despite normal insulin and glucose levels after refeeding. Higher levels of plasma insulin were required to support similar levels of hepatic lipogenesis de novo ((3)H(2)O incorporation) in the PPARalpha-null mice compared with the wild-type. This difference was reflected by corresponding changes in the relationship between plasma insulin and the mRNA expression of the lipogenic transcription factor sterol-regulatory-element-binding protein-1c, and that of one of its known targets, fatty acid synthase. In wild-type mice, hepatic pyruvate dehydrogenase kinase (PDK) 4 protein expression (a downstream marker of altered fatty acid catabolism) increased (P<0.01) in response to fasting, with suppression (P<0.001) by refeeding. Although PDK4 up-regulation after fasting was halved by PPARalpha deficiency, PDK4 suppression after refeeding was attenuated. In summary, PPARalpha deficiency leads to accumulation of hepatic TAG and elicits dysregulation of hepatic lipid and carbohydrate metabolism, emphasizing the importance of precise control of lipid oxidation for hepatic fuel homoeostasis.
authors.affiliation: Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, UK. m.c.sugden@qmul.ac.uk
authors.forename: Mary C
authors.initials: MC
authors.lastname: Sugden
authors.forename: Karen
authors.initials: K
authors.lastname: Bulmer
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Gibbons
authors.forename: Brian L
authors.initials: BL
authors.lastname: Knight
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Holness
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D050260:Carbohydrate Metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D013217:Starvation; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008055:Lipids; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D019014:fas Receptor; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases