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.