Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus

Kuzuya, Teiji; Katano, Yoshiaki; Nakano, Isao; Hirooka, Yoshiki; Itoh, Akihiro; Ishigami, Masatoshi; Hayashi, Kazuhiko; Honda, Takashi; Goto, Hidemi; Fujita, Yūkō; Shikano, Rie; Muramatsu, Yuji; Bajotto, Gustavo; Tamura, Tomohide; Tamura, Noriko; Shimomura, Yoshiharu

doi:10.1016/j.bbrc.2008.05.167

Cited by 59 publications

(59 citation statements)

References 10 publications

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“…Because BDK requires the E2 core for the bulk of kinase activity (11), abrogating BDK binding to LBD from the E2 core will deactivate the kinase. In support of this mechanism, the presence of KIC in HEK293T cells (13,37) or the dietary supplementation of BCAA in type 2 diabetes rat models (38) promotes the dissociation of BDK from the E2 core, resulting in the dephosphorylation of BCKDC.…”

Section: Discussionmentioning

confidence: 96%

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Tso¹,

Qi²,

Gui³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.branched-chain α-ketoacid dehydrogenase kinase inhibitor | structure-based inhibitor design | allosteric mechanisms | kinase-inhibitor complex structures | in vivo kinase inhibitor studies T he branched-chain amino acids (BCAA) leucine, isoleucine, and valine comprise 40% of essential amino acids in daily dietary intake (1). The catabolic pathways of BCAA begin with transamination by branched-chain aminotransferases giving rise to corresponding branch-chain α-ketoacids (BCKA). The second common step, the irreversible oxidative decarboxylation of BCKA, is catalyzed by the single mitochondrial branch-chain α-ketoacid dehydrogenase complex (BCKDC). The homeostasis of BCAA and BCKA in vivo is critical for health. The accumulation of BCAA and BCKA secondary to inherited BCKDC deficiency produces maple syrup urine disease (MSUD), which can lead to fatal acidosis, neurological derangement, and mental retardation (2, 3). In large-scale high-throughput metabolic profiling studies, high blood BCAA concentrations were found to be highly associated with the development of insulin resistance (4, 5) and can serve as useful metabolic markers in type 2 diabetes risk assessment (6, 7). Pathologic stresses produced by the accumulated BCKA are linked to congenital heart diseases and heart failure (8). The above findings underscore the pivotal role of aberrant BCAA metabolism in the pathogenesis of metabolic, cardiac, and neurological diseases.The 4.5-MDa human BCKDC consists of three catalytic components: a heterotetrameric (α 2 β 2 ) branched-chain α-ketoacid decarboxylase (E1), a homo-24 meric dihydrolipoyltransacylase (E2), and a homodimeric dihydrolipoamide dehydrogenase (E3). In addition, human BCKDC contains two regulatory enzymes: BCKD kinase (BDK) and BCKD phosphatase (BDP), the latter also called PP2Cm phosphatase; these enzymes tightly regulate activity of BCKDC through the phosphorylation (inactivation)/ dephosphorylation (activation) of the E1α subunits (9, 10). BCKDC is or...

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Section: Discussionmentioning

confidence: 96%

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Tso¹,

Qi²,

Gui³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies have reported that decreased BCKD activity causes downregulation of BCAA catabolism in diabetes (6,7,36). It also has demonstrated that BDK is responsible for phosphorylation and inactivation of BCKD complex and considered a primary regulator of BCKD activation (6).…”

Section: Discussionmentioning

confidence: 99%

Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice

et al. 2014

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The branched-chain amino acids (BCAA) accumulated in type 2 diabetes are independent contributors to insulin resistance. The activity of branched-chain a-keto acid dehydrogenase (BCKD) complex, rate-limiting enzyme in BCAA catabolism, is reduced in diabetic states, which contributes to elevated BCAA concentrations. However, the mechanisms underlying decreased BCKD activity remain poorly understood. Here, we demonstrate that mitochondrial phosphatase 2C (PP2Cm), a newly identified BCKD phosphatase that increases BCKD activity, was significantly downregulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin (APN) knockout (APN 2/2 ) mice fed with a high-fat diet (HD), PP2Cm expression and BCKD activity were significantly decreased, whereas BCKD kinase (BDK), which inhibits BCKD activity, was markedly increased. Concurrently, plasma BCAA and branched-chain a-keto acids (BCKA) were significantly elevated. APN treatment markedly reverted PP2Cm, BDK, BCKD activity, and BCAA and BCKA levels in HD-fed APN 2/2 and diabetic animals.Additionally, increased BCKD activity caused by APN administration was partially but significantly inhibited in PP2Cm knockout mice. Finally, APN-mediated upregulation of PP2Cm expression and BCKD activity were abolished when AMPK was inhibited. Collectively, we have provided the first direct evidence that APN is a novel regulator of PP2Cm and systematic BCAA levels, suggesting that targeting APN may be a pharmacological approach to ameliorating BCAA catabolism in the diabetic state.The branched-chain amino acids (BCAA) are essential amino acids such as leucine, isoleucine, and valine; their homeostasis is determined largely by catabolic activities in a number of organs including liver, muscle and adipose tissue (1-3). The first step of BCAA catabolism generates a set of corresponding branched-chain a-keto acids (BCKA), which are irreversibly decarboxylated by the branched-chain a-keto acid dehydrogenase (BCKD) complex (4). As with most nutrients, maintaining of the physiological level of BCAA is critical for cell metabolism and survival. However, many researchers have described increased BCAA and BCKA levels in diabetes and obesity (3,(5)(6)(7)(8). Furthermore, BCAA and their catabolites are strongly associated with insulin resistance (9-11), and elevated BCAA contributes to the development of insulin resistance (10,12). Mechanistically, elevated BCAA levels activate mTOR/p70S6 kinase, resulting in an increased I insulin receptor substrate-1 phosphorylation, thereby inhibiting phosphatidylinositol 3-kinase. This inhibition of phosphatidylinositol 3-kinase in turn leads to impaired insulin signaling (13,14). It is also reported that BCAA are independent predictors of insulin resistance, diabetes, and cardiovascular events (15-17). Therefore, it is necessary to determine the mechanisms of abnormal BCAA catabolism in order to better understand their association with metabolic-related pathogenesis. The BCKD complex is the rate-limiting enzyme in BCAA catabolism (4,12); regulation o...

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“…2E). Blunted branched-chain keto acid dehydrogenase (BCKDH) activity, observed in various models of obesity and T2DM (23,26,30), may be a contributing factor. However, we did not observe any impairment in BCKDH activity, which could manifest with more severe hepatic insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease

Sunny

Kalavalapalli

Bril

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD.

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Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus

Cited by 59 publications

References 10 publications

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Impaired Adiponectin Signaling Contributes to Disturbed Catabolism of Branched-Chain Amino Acids in Diabetic Mice

Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease

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