scholarly journals BS32 The role of branched-chain keto acids in mediating insulin resistance in the failing heart

2021 ◽  
Author(s):  
Qutuba Karwi ◽  
Cory Wagg ◽  
Liyan Zhang ◽  
John Ussher ◽  
Gary Lopaschuk
Keyword(s):  
Insulin Resistance ◽  
Failing Heart ◽  
Keto Acids ◽  
Branched Chain ◽  
Branched Chain Keto Acids

Abstract MP125: Branched-chain Keto Acids, Not Branched-chain Amino Acids, Impairs Cardiac Insulin Sensitivity by Disrupting Insulin Signaling in the Mitochondria

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Qutuba Karwi ◽  
Golam Mezbah Uddin ◽  
Cory S Wagg ◽  
Gary D Lopaschuk
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Insulin Sensitivity ◽  
Glucose Oxidation ◽  
Branched Chain Amino Acids ◽  
Mitochondrial Translocation ◽  
Oxidation Rates ◽  
Keto Acids ◽  
Branched Chain ◽  
Branched Chain Keto Acids

Alterations in branched-chain amino acids (BCAA) oxidation have been linked to the development of cardiac insulin resistance and its negative impact on cardiac function. However, it is not clear if these detrimental effects are due to the accumulation of BCAAs or branched-chain keto acids (BCKAs). It is also unknown how impaired BCAAs oxidation mediates cardiac insulin resistance. To examine this, we specifically deleted mitochondrial branched-chain aminotransferase (BCATm) in the heart to selectively increase in BCAAs and decrease in BCKAs in the heart. BCATm -/- mice had normal cardiac function compared to their wildtype littermates (WT Cre+/+ ). However, there was a significant increase in insulin-stimulated cardiac glucose oxidation rates in BCATm -/- mice, independent of any changes in glucose uptake or glycolytic rates. This enhancement in cardiac insulin sensitivity was associated with an increase in the phosphorylation of Akt and activation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. To determine the impact of reversing these events, we examined the effects of increasing cardiac BCKAs on cardiac insulin sensitivity. We perfused isolated working mice hearts with high levels of BCKAs (α;-keto-isocaproate 80 μM, α;-keto-β;-methylvalorate 100μM, α;-keto-isovalorate 70 μM), levels that can be seen during diabetes and obesity. The BCKAs completely blunted insulin-stimulated glucose oxidation rates. We also found that BCKAs abolished insulin-stimulated mitochondrial translocation of Akt, an effect which was associated with PDH deactivation. We conclude that the accumulation of BCKAs, and not BCAAs, is a major contributor to cardiac insulin resistance via abrogating mitochondrial translocation of Akt.

Influence of branched-chain amino acids and branched-chain keto acids on protein synthesis in isolated hepatocytes

Hepatology ◽  
1987 ◽  
Vol 7 (2) ◽  
pp. 324-329 ◽  
Author(s):  
Wolfgang Base ◽  
Carl Barsigian ◽  
Alisa Schaeffer ◽  
Ellen Shaw ◽  
Jose Martinez ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Isolated Hepatocytes ◽  
Branched Chain Amino Acids ◽  
Keto Acids ◽  
Branched Chain ◽  
Branched Chain Keto Acids

Transamination of branched-chain keto acids by isolated perfused rat kidney.

1978 ◽  
Vol 235 (1) ◽  
pp. E47
Author(s):  
W E Mitch ◽  
W Chan
Keyword(s):  
Amino Acids ◽  
Rat Kidney ◽  
Branched Chain Amino Acids ◽  
Keto Acid ◽  
Branched Chain Amino Acid ◽  
Keto Acids ◽  
Perfused Rat Kidney ◽  
Branched Chain ◽  
Branched Chain Keto Acids ◽  
Isolated Rat

Isolated rat kidney perfused without substrate released serine, glycine, and taurine, and substantially smaller amounts of other amino acids. When branched-chain keto acids were added, the corresponding amino acids were released at rates amounting to 15-25% of keto acid disappearance. Perfusion with 2 mM alpha-keto-isovalerate or alpha-keto-beta-methylvalerate caused an increased glucose release amounting to 18-23% of keto acid disappearance. The activity of branched-chain amino acid transferase (BATase) was significantly stimulated by perfusion with the analogue of leucine, but not by perfusion with alpha-ketoglutarate, the analogues of valine or isoleucine, or with leucine itself. These findings document that the kidney converts branched-chain keto acids in part to the corresponding amino acids and suggest that the keto analogue of leucine may be involved in the control of renal BATase activity, thereby indirectly regulating the metabolism of branched-chain amino acids.

scholarly journals Branched-Chain Keto-Acids and Pyruvate in Blood: Measurement by HPLC with Fluorimetric Detection and Changes in Older Subjects

2000 ◽  
Vol 46 (6) ◽  
pp. 848-853 ◽  
Author(s):  
Karine Pailla ◽  
Françoise Blonde-Cynober ◽  
Christian Aussel ◽  
Jean-Pascal De Bandt ◽  
Luc Cynober
Keyword(s):  
Young Adults ◽  
Age Groups ◽  
Reversed Phase ◽  
Fluorometric Detection ◽  
Institutionalized Elderly ◽  
Keto Acids ◽  
Significant Difference ◽  
Branched Chain ◽  
Branched Chain Keto Acids

Abstract Background: Measurement of keto-acids is important in various clinical situations. The aim of the present work was to develop a rapid HPLC method for the determination of keto-acids in human serum and to assess the concentrations of these acids in young adults and institutionalized elderly adults. This method was applied to the determination of blood keto-acid concentrations of young adults and institutionalized elderly people, divided into age groups Methods: Four keto-acids (α-ketoisocaproate, α-ketoisovalerate, α-keto-β-methylvalerate, and pyruvate) were derivatized with o-phenylenediamine to give fluorescent derivatives. After the sample preparation step (75 min to prepare 20 samples), the derivatives were separated chromatographically on a reversed-phase column using a binary gradient. Results: The fluorometric detection of the four keto-acids was rapid, <12 min. The method is repeatable and reproducible: the CVs were <6% and <11%, respectively, for each of the keto-acids. We found no significant difference between males and females. Concentrations of the branched-chain keto-acids decreased after age 60 years, especially α-ketoisocaproate, which decreased ∼40%. Conclusions: The proposed method allows rapid and reliable measurement of keto-acids. The data demonstrate that changes in branched-chain keto-acids concentrations in serum occur with age.

New tools for an old question: dependence of ATP and bicarbonate for branched-chain keto acids oxidation

2019 ◽  
Vol 476 (15) ◽  
pp. 2235-2237
Author(s):  
Henver S. Brunetta ◽  
Graham P. Holloway
Keyword(s):  
Energy Production ◽  
Acid Oxidation ◽  
Methodological Issues ◽  
Amino Acid Oxidation ◽  
Branched Chain Amino Acid ◽  
Biochemical Journal ◽  
Keto Acids ◽  
Branched Chain ◽  
Branched Chain Keto Acids

Abstract Branched-chain keto acids (BCKA) metabolism involves several well-regulated steps within mitochondria, requires cofactors, and is modulated according to the metabolic status of the cells. This regulation has made it challenging to utilize in vitro approaches to determine the contribution of branched-chain amino acid oxidation to energy production. These methodological issues were elegantly addressed in a recent publication within the Biochemical Journal. In this issue, Goldberg et al. [Biochem. J. (2019) 476, 1521–1537] demonstrated in a well-designed system the dependence of ATP and bicarbonate for BCKA full oxidation. In addition, the utilized system allowed the authors to characterize specific biochemical routes within mitochondria for each BCKA. Among them, a quantitative analysis of the participation of BCKA on mitochondrial flux was estimated between tissues. These findings are milestones with meaningful impact in several fields of metabolism.

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