{"doi":"10.1016/j.jbc.2022.102648","title":"Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet","abstract":"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 (PcxL−/−) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL−/− 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 PcxL−/− mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL−/− 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 PcxL−/− 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. 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 (PcxL−/−) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL−/− 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 PcxL−/− mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL−/− 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 PcxL−/− 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. The liver can exhibit dramatic metabolic shifts depending on nutritional and/or dietary state. This metabolic flexibility is most aptly demonstrated by the shift between ad libitum feeding and fasting where the liver becomes a net consumer or producer of blood glucose, respectively (1Rui L. Energy metabolism in the liver.Compr. Physiol. 2014; 4: 177-197Crossref PubMed Scopus (1243) Google Scholar). Conversely, the liver is a net producer and then consumer of fatty acids between the carbohydrate replete and fasted states. This shift in macronutrient metabolism is accomplished by shifts in tricarboxylic acid (TCA) cycle flux whereby carbon is partitioned into either the reductive or oxidative branches of the TCA cycle to facilitate gluconeogenesis or fatty acid synthesis. While the fate of pyruvate is unique among the fed and fasted states, pyruvate carboxylase is central to both by generating oxaloacetate (OAA) from pyruvate (2Utter M.F. Keech D.B. Formation of oxaloacetate from pyruvate and carbon dioxide.J. Biol. Chem. 1960; 235: PC17-PC18Abstract Full Text PDF PubMed Google Scholar). Pyruvate entry into mitochondria is accompanied by the concomitant partitioning of pyruvate into two major fates, the oxidative decarboxylation to acetyl-CoA and CO2 via the pyruvate decarboxylase complex or its","journal":"Journal of Biological Chemistry","year":2022,"id":252972,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":898210,"name":"Susana Rodriguez","orcid":"0000-0002-2254-0249","position":1,"is_corresponding":false},{"id":820883,"name":"Kyle Cavagnini","orcid":"0009-0006-5818-9856","position":2,"is_corresponding":false},{"id":898211,"name":"Han-Byeol Kim","orcid":"0000-0002-6190-1078","position":3,"is_corresponding":false},{"id":305261,"name":"Chan Hyun Na","orcid":"0000-0002-3622-2938","position":4,"is_corresponding":false},{"id":381090,"name":"Michael J. Wolfgang","orcid":"0000-0003-2349-8414","position":5,"is_corresponding":false},{"id":381089,"name":"Ebru S. Selen Alpergin","orcid":"0000-0002-4345-3945","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T00:24:55.325369Z","pmid":"36441025","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}