Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation

ArticleinAJP Endocrinology and Metabolism 304(4) · December 2012with25 Reads
DOI: 10.1152/ajpendo.00547.2012 · Source: PubMed
Abstract
During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme CoA transferase (succinyl-CoA:3-oxoacid CoA transferase, SCOT, encoded by nuclear Oxct1) is required for oxidation of ketone bodies, and that germline SCOT-knockout (KO) mice die within 48h of birth due to hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. While transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes, are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1(+/-) mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.
    • "Interestingly, on the other hand, newborns lacking SCOT–and hence having impaired ketone body oxidation–develop hyperketonemic hypoglycemia and die perinatally as a result of energy imbalance and acidosis [9] . Conversely, mice with tissue-specific deletion of SCOT in neurons, heart or skeletal muscle present some alteration in metabolic parameters but they survive the early neonatal period, the adherence to a ketogenic diet, and moderate starvation [10] . However, deficiency of myocardial ketone body oxidation predisposes the heart more sensitive to redox imbalance and oxidative stress during pressure overload-induced cardiac injury [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Ketone bodies β-hydroxybutyrate (BHB) and acetoacetate are important metabolic substrates for energy production during prolonged fasting. However, BHB also has signaling functions. Through several metabolic pathways or processes, BHB modulates nutrient utilization and energy expenditure. These findings suggest that BHB is not solely a metabolic intermediate, but also acts as a signal to regulate metabolism and maintain energy homeostasis during nutrient deprivation. We briefly summarize the metabolism and emerging physiological functions of ketone bodies and highlight the potential role for BHB as a signaling molecule in starvation response.
    Article · Apr 2016
    • "The classic ketogenic diet is a high-fat and low-carbohydrate diet, which can produce acetoacetate, 3-hydroxybutyrate and acetone. Mitochondrial Bdh1 re-oxidizes D-βhydroxybutyrate to acetoacetate, and Oxct1 catalyzes the covalent activation of acetoacetate by coenzyme A to generate acetoacetate- CoA in extrahepatic tissues (Cotter et al., 2013; Hori et al., 2013). Up-regulated Oxct1 and Bdh in fish fed the HFD are required to convert ketone bodies to acetyl-CoA for terminal oxidation in the tricarboxylic acid cycle. "
    [Show abstract] [Hide abstract] ABSTRACT: Blunt snout bream (Megalobrama amblycephala), a prevalent species in China's intensive polyculture systems, is highly susceptible to hepatic steatosis, resulting in considerable losses to the fish farming industry. Due to a lack of genomic resources, the molecular mechanisms of lipid metabolism in M. amblycephala are poorly understood. Here, a hepatic cDNA library was generated from equal amounts of mRNAs isolated from M. amblycephala fed normal-fat and high-fat diets. Sequencing of this library using the Illumina/Solexa platform produced approximately 51.87 million clean reads, which were assembled into 48,439 unigenes with an average length of 596bp and an N50 value of 800bp. These unigenes were searched against the nucleotide (NT), non-redundant (NR), Swiss-Prot, Cluster of Orthologous Groups (COG), and Kyoto Encyclopedia of Genes and Genome (KEGG) databases using the BLASTn or BLASTx algorithms (E-value≤10(-5)). A total of 8,602 unigenes and 22,155 unigenes were functionally classified into 25 COG categories and 259 KEGG pathways, respectively. Furthermore, 22,072 unigenes were grouped into 62 sub-categories belonging to three main Gene Ontology (GO) terms. Using a digital gene expression analysis and the M. amblycephala transcriptome as a reference, 477 genes (134 up-regulated and 343 down-regulated) were identified as differentially expressed in fish fed a high-fat diet versus a normal-fat diet. KEGG and GO functional enrichment analyses of the differentially expressed unigenes were performed and 12 candidate genes related to lipid metabolism were identified. This study provides a global survey of hepatic transcriptome profiles and identifies candidate genes that may be related to lipid metabolism in M. amblycephala. These findings will facilitate further investigations of the mechanisms underlying hepatic steatosis in M. amblycephala. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015
    • "In the mitochondria, acetoacetate is activated by coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT); EC 2.8.3.5] to acetoacetyl-CoA, which is then converted to acetylcoA and introduced into the tricarboxylic acid (TCA) cycle for energy production. SCOT knockout mice exhibit marked hyperketonemia, showing the importance of the appropriate regulation of ketone body metabolism during the neonatal period [3,6]. In the cytosol, acetoacetate is converted to acetoacetyl-CoA by acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16) "
    [Show abstract] [Hide abstract] ABSTRACT: Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme, which is responsible for the synthesis of cholesterol and fatty acids from ketone bodies in lipogenic tissues, such as the liver and adipocytes. To explore the possibility of AACS regulation at the protein-processing level, we investigated the proteolytic degradation of AACS. Western blot analysis showed that the 75.1 kDa AACS was cleaved to form a protein of approximately 55 kDa in the kidney, which has considerable high activity of legumain, a lysosomal asparaginyl endopeptidase. Co-expression of AACS and legumain in HEK 293 cells generated the 55 kDa product from AACS. Moreover, incubation of recombinant AACS with recombinant legumain resulted in the degradation of AACS. Knockdown of legumain with short-hairpin RNA against legumain using the hydrodynamics method led to a decrease in the 55 kDa band of AACS in mouse kidney. These results suggest that legumain is involved in the processing of AACS through the lysosomal degradation pathway in the kidney.
    Article · Oct 2014
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