title: Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway.
abstract: During the absorptive state, the liver stores excess glucose as glycogen and synthesizes fatty acids for triglyceride synthesis for export as very low density lipoproteins. For de novo synthesis of fatty acids from glucose, the mitochondrial pyruvate dehydrogenase complex (PDC) is the gatekeeper for the generation of acetyl-CoA from glucose-derived pyruvate. Here, we tested the hypothesis that limiting the supply of PDC-generated acetyl-CoA from glucose would have an impact on expression of key genes in the lipogenic pathway. In the present study, although the postnatal growth of liver-specific PDC-deficient (L-PDCKO) male mice was largely unaltered, the mice developed hyperinsulinemia with lower blood glucose levels in the fed state. Serum and liver lipid triglyceride and cholesterol levels remained unaltered in L-PDCKO mice. Expression of several key genes (ACL, ACC1) in the lipogenic pathway and their upstream regulators (LXR, SREBP1, ChREBP) as well as several genes in glucose metabolism (Pklr, G6pd2, Pck1) and fatty acid oxidation (FAT, Cpt1a) was downregulated in livers from L-PDCKO mice. Interestingly, there was concomitant upregulation of lipogenic genes in adipose tissue from L-PDCKO mice. Although, the total hepatic acetyl-CoA content remained unaltered in L-PDCKO mice, modified acetylation profiles of proteins in the nuclear compartment suggested an important role for PDC-generated acetyl-CoA in gene expression in de novo fatty acid synthesis in the liver. This finding has important implications for the regulation of hepatic lipid synthesis in pathological states.
authors.affiliation: Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, and.
authors.forename: Saleh
authors.initials: S
authors.lastname: Mahmood
authors.affiliation: Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Birkaya
authors.affiliation: Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Rideout
authors.affiliation: Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, and mspatel@buffalo.edu.
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013347:Subcellular Fractions; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D014280:Triglycerides; D000105:Acetyl Coenzyme A; D002784:Cholesterol; D005947:Glucose
keywords: acetyl-CoA; gene expression; lipogenic pathway; liver-specific pyruvate dehydrogenase complex-deficient mice; nuclear protein acetylation