| First Author | Selen ES | Year | 2022 |
| Journal | J Biol Chem | Volume | 298 |
| Issue | 12 | Pages | 102648 |
| PubMed ID | 36441025 | Mgi Jnum | J:332296 |
| Mgi Id | MGI:7410137 | Doi | 10.1016/j.jbc.2022.102648 |
| Citation | Selen ES, et al. (2022) Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet. J Biol Chem 298(12):102648 |
| abstractText | Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (Pcx(L-/-)) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. Pcx(L-/-) mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to Pcx(L-/-) mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that Pcx(L-/-) mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in Pcx(L-/-) mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways. |
