Mitochondria‐Generated Acetyl‐CoA Regulates Gene Expression in Hepatic Lipid Synthesis

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) plays a gatekeeper's role for generation of the carbon‐flux as acetyl‐CoA. We have shown previously that there was no incorporation of radioactive glucose‐carbon into newly synthesized fatty acids in livers from liver‐specific PDC‐deficient male mice (L‐PDHKO) due to the null mutation of the Pdha1 gene. In the present study, although the postnatal growth of L‐PDHKO mice was largely unaltered, they developed hyperinsulinemia with lower blood glucose levels in the fed state. Serum and liver lipid triglyceride and cholesterol levels remained unaltered in L‐PDHKO mice. To determine the effect of liver‐specific PDC deficiency on lipid and glucose metabolism, we investigated expression of several key genes as well as their upstream regulators in lipid and glucose metabolism. Interestingly, there was significant downregulation of expression of several key genes (such as ATP‐citrate lyase, acetyl‐CoA carboxylase) in the de novo fatty acid synthesis pathway and their upstream regulators (such as LXR, SREBP1, ChREBP). Downregulation of several genes in the metabolism of glucose (glucose‐6‐phosphate dehydrogenase, pyruvate kinase, phosphoenolpyruvate carboxykinase) and fatty acid oxidation (fatty acid transporter, carnitine‐palmitoyl‐CoA transferase‐1) were also observed in livers of L‐PDHKO mice. Interestingly, there was upregulation of lipogenic genes in epididymal adipose tissue from L‐PDHKO mice. Although, the total hepatic acetyl‐CoA content remained unaltered in these mice, modified acetylation profiles of several proteins in the nucleo‐cytoplasmic compartment (including increased level of acetylated histone3lysine9, H3K9) in livers of L‐PDHKO mice suggest an important role of mitochondria‐generated acetyl‐CoA from glucose‐derived pyruvate by PDC in gene expression in hepatic lipid metabolism. This finding has important implications for regulation of hepatic lipid biosynthesis in obesity, type 2 diabetes and non‐alcoholic fatty liver disease.Support or Funding Information(Supported in part by NIH Grant DK20478 and Department Fund, The Research Foundation of The State University of New York.)