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- Coupling of Mitochondrial Fatty Acid Uptake to Oxidative Flu...Coupling of Mitochondrial Fatty Acid Uptake to Oxidative Flux in the Intact Heart
Biophysical Journal, Volume 82, Issue 1, 1 January 2002, Pages 11-18
J. Michael O’Donnell, Nathaniel M. Alpert, Lawrence T. White and E. Douglas Lewandowski
AbstractThe coordination of long chain fatty acid (LCFA) transport across the mitochondrial membrane () with subsequent oxidation rate through -oxidation and the tricarboxylic acid (TCA) cycle () has been difficult to characterize in the intact heart. Kinetic analysis of dynamic C-NMR distinguished these flux rates in isolated rabbit hearts. Hearts were perfused in a 9.4 T magnet with either 0.5mM [2,4,6,8,10,12,14,16-C] palmitate (=4), or 0.5mM C-labeled palmitate plus 0.08mM unlabeled butyrate (=4). Butyrate is a short chain fatty acid (SCFA) that bypasses the LCFA transporters of mitochondria. In hearts oxidizing palmitate alone, the ratio of to was 8:1. This is consistent with one molecule of palmitate yielding eight molecules of acetyl-CoA for the subsequent oxidation through the TCA cycle. Addition of butyrate elevated this ratio; /=12:1 due to an SCFA-induced increase in of 43% (<0.05). However, SCFA oxidation did not significantly reduce palmitate transport into the mitochondria: =1.0±0.2mol/min/g dw with palmitate alone versus 0.9±0.1 with palmitate plus butyrate. Thus, the products of -oxidation are preferentially channeled to the TCA cycle, away from mitochondrial efflux via carnitine acetyltransferase.
Abstract | Full Text | PDF (132 kb) - Butyrate and related inhibitors of histone deacetylation blo...Butyrate and related inhibitors of histone deacetylation block the induction of egg white genes by steroid hormones
Cell, Volume 22, Issue 2, 1 November 1980, Pages 469-477
G. Stanley McKnight, Lisa Hager and Richard D. Palmiter
SummaryThe short chain aliphatic acid salts, butyrate and propionate, are effective inhibitors of histone deacetylation in chick oviduct at 2–5 mM; they also prevent the hormonal induction of the ovalbumin and transferrin genes. The less potent deacetylase inhibitor isobutyrate is correspondingly less effective in blocking egg white mRNA induction; acetate has little effect at concentrations up to 15 mM. Butyrate does not appear to alter estrogen receptor binding in the nucleus, total RNA synthesis, or protein synthesis during the early hours of treatment when its specific effects on deacetylation and egg white gene transcription are observed. In addition to preventing the induction, butyrate also causes a rapid deinduction when added to preinduced cultures; ovalbumin and transferrin gene transcription decline with a half-life of 15–30 min. The effects of butyrate on egg white mRNA induction and deacetylation are completely reversible, and mRNA induction resumes within 1 hr after removal of butyrate from the medium. These results suggest that the modification of either histones or other unidentified regulatory proteins by acetylation may play a role in the mechanism of estrogen-mediated gene induction.
Summary | PDF (1396 kb) - Sodium butyrate inhibits histone deacetylation in cultured c...Sodium butyrate inhibits histone deacetylation in cultured cells
Cell, Volume 14, Issue 1, 1 May 1978, Pages 105-113
E.Peter M. Candido, Raymond Reeves and James R. Davie
SummarySodium butyrate in millimolar concentrations causes an accumulation of acetylated histone species in a variety of vertebrate cell lines. In all lines tested, butyrate caused hyperacetylation of H3 and H4, and in rat IRC8 cells, H2A and H2B were also affected. In Friend erythroleukemic cells, butyrate also induces the synthesis of a nonhistone chromosomal protein, IP. Butyrate does not affect the rate of histone acetylation in cell-free extracts or nuclei of Friend cells. Rather, this fatty acid inhibits histone deacetylation. Cell-free extracts of either control cells or butyrate-grown cells contain comparable levels of histone-deacetylating activity. This in vitro activity is inhibited by the addition of butyrate to the extracts. Thus butyrate appears to be an inhibitor of histone deacetylases both in vivo and in vitro.
Summary | PDF (2748 kb) - …more
Copyright © 1995 The Biophysical Society. All rights reserved.
Biophysical Journal, Volume 69, Issue 5, 2090-2102, 1 November 1995
doi:10.1016/S0006-3495(95)80080-9
Research Article
Kinetic analysis of dynamic 13C NMR spectra: metabolic flux, regulation, and compartmentation in hearts
X. Yu, L.T. White, C. Doumen, L.A. Damico, K.F. LaNoue, N.M. Alpert and E.D. Lewandowski
NMR Center, Massachusetts General Hospital, Boston, USA.
Abstract
Control of oxidative metabolism was studied using 13C NMR spectroscopy to detect rate-limiting steps in 13C labeling of glutamate. 13C NMR spectra were acquired every 1 or 2min from isolated rabbit hearts perfused with either 2.5 mM [2–13C]acetate or 2.5 mM [2–13C]butyrate with or without KCl arrest. Tricarboxylic acid cycle flux (VTCA) and the exchange rate between alpha-ketoglutarate and glutamate (F1) were determined by least-square fitting of a kinetic model to NMR data. Rates were compared to measured kinetics of the cardiac glutamate-oxaloacetate transaminase (GOT). Despite similar oxygen use, hearts oxidizing butyrate instead of acetate showed delayed incorporation of 13C label into glutamate and lower VTCA, because of the influence of beta-oxidation: butyrate = 7.1 +/- 0.2 mumol/min/g dry wt; acetate = 10.1 +/- 0.2; butyrate + KCl = 1.8 +/- 0.1; acetate + KCl = 3.1 +/- 0.1 (mean +/- SD). F1 ranged from a low of 4.4 +/- 1.0 mumol/min/g (butyrate + KCl) to 9.3 +/- 0.6 (acetate), at least 20-fold slower than GOT flux, and proved to be rate limiting for isotope turnover in the glutamate pool. Therefore, dynamic 13C NMR observations were sensitive not only to TCA cycle flux but also to the interconversion between TCA cycle intermediates and glutamate.
