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Regulation of Branched-Chain -Keto Acid Dehydrogenase Kinase Expression in Rat Liver^{1 ,2}

Robert A. Harris^*3, Rumi Kobayashi, Taro Murakami^*,** and Yoshiharu Shimomura^**

^* Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, Department of Nutrition and Food Science, Ochanomizu University, Tokyo 112-8610, Japan, and ^** Department of Bioscience, Nagoya Institute of Technology, Showa-ku, Nagoya 466-8555, Japan

³To whom correspondence should be addressed at Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Drive, Indianapolis, IN 46202-5122. E-mail: raharris{at}iupui.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Branched-chain amino acids are toxic in excess but have to be conserved for protein synthesis. This is accomplished in large part by control of the activity of the branched-chain -keto acid dehydrogenase complex by phosphorylation/dephosphorylation. Regulation of the activity of the hepatic enzyme appears particularly important, at least in rats, since an exceptional high activity of the complex in this tissue makes the liver the primary clearing house for excess branched-chain -keto acids released by other tissues. The degree to which the branched-chain -keto acid dehydrogenase complex is inactivated by phosphorylation is determined by the activity of the branched-chain -keto acid dehydrogenase kinase, which is itself regulated by allosteric effectors as well as factors that affect its level of expression. Well established among these are the -keto acid produced by leucine transamination, which is a potent inhibitor of the kinase, and starvation for dietary protein, which causes increased expression of the branched-chain -keto acid dehydrogenase kinase. The latter finding resulted in the working hypothesis that nutrients and hormones regulate expression of the branched-chain -keto acid dehydrogenase kinase. Evidence has been obtained for the involvement of thyroid hormone, glucocorticoids and ligands for peroxisome proliferator-activated receptor . Thyroid hormone induces, whereas glucocorticoids and peroxisome proliferator-activated receptor ligands repress, expression of the kinase. Increased blood levels of thyroid hormone are proposed to be responsible for increased expression of branched-chain -keto acid dehydrogenase kinase in animals starved for protein.

KEY WORDS: • branched-chain amino acids • kinase • dehydrogenase • leucine • rat • liver

	INTRODUCTION

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Disposal of dietary branched-chain amino acids (BCAAs)⁴ present in excess above that needed for replacement protein synthesis is necessary to prevent the pathological consequences of maple syrup urine disease. On the other hand, because animals cannot synthesize BCAAs, it is just as important to have a means to shut off BCAA disposal to ensure their continuous availability for protein synthesis. Likewise it is important to regulate leucine disposal because of its unique stimulatory effect on protein synthesis (Anthony et al. 2000 ). It follows therefore that nature has evolved multiple mechanisms to control the activity of the enzyme responsible for the committed step in BCAA catabolism, the branched-chain -keto acid dehydrogenase complex (BCKDC).

	The branched-chain -keto acid dehydrogenase complex

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
BCKDC catalyzes the oxidative decarboxylation of branched-chain -keto acids (BCKAs), and is the rate limiting, irreversible step of the pathways for leucine, isoleucine and valine catabolism. The complex has three components: 1) a specific dehydrogenase (E1; ₂ß₂ heterotetramer; 12 per complex), 2) a specific transacylase (E2; 24-oligomer; core of the complex) and 3) dihydrolipoamide dehydrogenase (E3; ₂ homodimer; six per complex). The molecular weight of the complex is about 3.5 million. Two regulatory enzymes are associated with BCKDC. The BCKDC kinase (BDK), which is active when bound, catalyzes the phosphorylation of two serine residues (Ser293 and Ser303) of the E1 subunit, which completely inactivates the E1 component. The BCKDC phosphatase, which is still not well characterized in terms of regulation and relationship to other phosphatases, catalyzes dephosphorylation and activation of the E1 component of the complex (Damuni and Reed 1987 ).

	Regulation of the branched-chain -keto acid dehydrogenase complex

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Like many other enzymes located at rate-determining steps in metabolic pathways, control of flux through BCKDC involves integration between facile ligand binding and regulation by a more complex phosphorylation/dephosphorylation mechanism. The products of BCKDC, that is, NADH and the CoA esters originating from the oxidative decarboxylation of BCKAs, can limit BCKDC activity by direct inhibitory effects. The extent to which the complex is dephosphorylated and therefore catalytically active depends on the relative activities of BDP and BDK. Regulation of BDP is an enigma that waits cloning and the generation of tools to study this enzyme at the molecular level. BDK is subject to robust inhibition by -ketoisocaproate, the BCKA produced from leucine by transamination. This negative allosteric effect on the kinase is believed important for short-term regulation of BCKDC activity (Harris et al. 1985 , 1990 ). An increase in blood leucine, originating either from the diet or from proteolysis of tissue protein, results in an increase in the intracellular concentration of -ketoisocaproate, provided conditions are right for cellular leucine uptake and intracellular transamination. -Ketoisocaproate directly inhibits BDK activity, thereby allowing dephosphorylation of E1 by BCKDC phosphatase and indirectly increasing BCKDC activity. The mitochondrial localization of branched-chain aminotransferase in most tissues (Hutson et al. 1992 ) means that transamination of leucine with -ketoisocaproate production occurs in the same compartment in which BCKDC is located, which should make for tight coupling of the two activities. Greater BCKDC activity causes irreversible degradation of the BCAAs. Conversely, when a decrease in -ketoisocaproate occurs because of a deficit in dietary leucine or a rapid rate of protein synthesis, a lower concentration of -ketoisocaproate causes less inhibition of BDK activity, resulting in a greater degree of phosphorylation and inactivation of BCKDC, thereby preserving BCAA for protein synthesis.

Feeding rats a low protein diet for several days causes downregulation of BCKDC, as measured by total enzyme activity and the amounts of the individual subunits (Zhao et al. 1994 ). The E1 component is downregulated more than is the E2 component, resulting in less than a full complement of E1 components relative to the other components of the complex in the liver of rats starved for protein. This further limits BCKDC activity because the E1 component is responsible for the rate-limiting step of the overall reaction catalyzed by the complex. On the other hand, more E1 components than can be bound by the complex are present in rats fed a high protein diet. The latter explains the occurrence of free E1, originally termed "BCKDH activator protein," in the mitochondrial matrix space (Espinal et al. 1985 ). Although free E1 can activate BCKDC by exchanging with inactive, phosphorylated E1 bound to the complex, it remains unclear whether free E1 serves a regulatory function for BCKDC activity.

Perhaps the most important mechanism for regulation of the BCKDC involves increased expression of BDK. This increases the amount of kinase bound to the complex, thereby increasing the extent to which the complex is phosphorylated and inactivated. Studies designed to provide the tools necessary to study regulation of BDK expression revealed that BDK belongs to a special family that includes the protein kinases responsible for regulation of the pyruvate dehydrogenase complex (PDC).

	The mitochondrial protein kinases

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Five mitochondrial protein kinases, corresponding to BDK and four pyruvate dehydrogenase kinase (PDK) isoenzymes, all encoded by separate nuclear genes, are expressed in eurkaryotic cells (Popov et al. 1992 , 1993 , 1994 , Harris et al. 1995 , 1997 ). The mitochondrial protein kinases are unique among kinases of eukaryotes. Their primary structure resembles that of histidine-protein kinases of prokaryotes rather than Ser/Thr-specific kinases of eukaryotes. The signature sequence motifs found in the cytosolic Ser/Thr protein kinases of eukaryotes are missing from the mitochondrial protein kinases. Nevertheless they all have regions of sequence in their C-termini that are also highly conserved in prokaryotic histidine protein kinases. Although the catalytic mechanism of histidine protein kinases involves formation of a phosphorylated histidine residue, it remains uncertain whether phosphorylation of such a residue is involved in the catalytic mechanism of the mitochondrial protein kinases (Davie et al. 1995 , Thelen et al. 2000 ). Nevertheless, molecular modeling studies suggest that the putative catalytic domain of the mitochondrial protein kinases probably folds in a manner similar to that of the histidine protein kinases (Bowker-Kinley and Popov 1999 ). Thus, genes encoding the mitochondrial kinases most likely originated from genes of bacteria endocytosed by primitive eukaryotic cells.

	Protein starvation upregulates BDK expression

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Regulation of BDK expression provides an important mechanism for conservation of BCAA in rats fed low protein diets (Harper et al. 1984 , Harris et al. 1990 ). The first evidence for such a mechanism came from studies with rats starved for dietary protein (Espinal et al. 1986 ). A stable increase in liver BDK activity was observed that could not be explained by allosteric effectors. This was subsequently shown to be the result of an increase in the amount of BDK protein associated with the complex (Popov et al. 1995 ). This finding along with a marked increase in steady-state level of BDK message in the liver of low protein–fed rats (Popov et al. 1995 , Huang and Chuang 1999 ) suggests control of BDK expression by a pretranslational mechanism. Increased kinase protein bound to BCKDC correlates with increased kinase activity associated with the complex and presumably accounts for decreased hepatic BCKDC activity. Rats fed a high protein diet, which is usually the case with laboratory diets, provide a model for examining factors that may cause upregulation of BDK expression. Conversely, feeding a 9% or lower protein diet provides a model for examining factors that cause downregulation of BDK expression.

	Starvation and diabetes downregulate BDK expression

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Starvation for food and starvation for protein, the latter imposed on rats by feeding a low protein diet, have opposite effects on the activity state of BDKDC (Harris et al. 1985 ) as well as the activity of its kinase (Kobayashi et al. 1999 ). Starvation for all food causes activation of liver BCKDC in animals in which the complex is normally phosphorylated and inactive (low protein–fed male rats or laboratory diet–fed female rats killed at the end of the light cycle). BDK activity is reduced by starvation for food in both models, suggesting changes in factors that cause downregulation of BDK expression. This stands in contrast to inactivation of BCKDC and upregulation of BDK expression in protein-starved rats. Experimentally induced diabetes in the rat likewise increases the activity state of hepatic BCKDC, which correlates with decreased BDK activity and protein (Lombardo et al. 1998 , 1999 ). Interestingly, the relative abundance of BDK message is not altered, suggesting regulation of expression by a posttranscriptional mechanism.

Starvation and diabetes have opposite effects on PDC and PDK relative to the effects described above for BCKDC and BDK. Starvation and diabetes increase PDK activity and therefore decrease PDC activity state in rat heart, skeletal muscle and liver (Kerbey and Randle, 1982 , Priestman et al. 1992 ). Like the changes induced in BDK by protein starvation, the increase in PDK induced by starvation and diabetes is stable during purification and therefore independent of the effects of the short-term regulatory molecules (acetyl-CoA, NADH and pyruvate). Increased expression of specific PDK genes is now known to be responsible for the increase PDK activity in several tissues of starved and diabetic rats (Wu et al. 1998 , 1999 , 2000 ). PDK isoform 4 (PDK4), measured at both the protein and transcript level, is greatly increased in the heart and skeletal muscle, whereas both PDK isoform 2 (PDK2) and PDK4 are increased in liver, kidney and lactating mammary gland by starvation and diabetes. Refeeding and insulin treatment reverse the increases in PDK2 and PDK4 protein and message levels in starved and diabetic animals, respectively. It follows from these findings that increased expression of specific PDK isoforms is a major determinant of the activity state of PDC and therefore the capacity that many tissues of the body have for the oxidation of glucose, lactate, alanine and pyruvate.

	A major difference in BCKDC regulation between male and female rats

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Female rats, rarely used for studies in this field, exhibit a remarkable difference in BCKDC regulation that suggests a role for estrogen in regulation of BDK activity. A diurnal rhythm occurs in the activity state of the hepatic BCKDC in female but not male rats (Kobayashi et al. 1997 , 1999 , Doering et al. 1998 ), suggesting factors that change in a cyclic manner throughout the time course of the day are involved in BCKDC regulation. At the beginning of the light cycle most of the BCKDC is in its dephosphorylated active form in both males and females. By the end of the light period most of the complex is phosphorylated and inactive in females, whereas it remains mostly dephosphorylated and active in males. The mechanism involves an increase in BDK activity between morning and evening that occurs specifically in females. An increase in the amount of BDK protein associated with the complex is responsible for the increase in activity. Gonadectomy prevents the diurnal rhythm in female rats, implicating the involvement of female sex hormones in the mechanism. The dramatic swings in BCKDC activity state and BDK activity occurring over the course of the day in female rats provide another useful model system for studying factors that affect the activities of these enzymes.

	Glucocorticoids downregulate BDK expression

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Liver BDK message levels are dramatically downregulated by the treatment of rats fed low protein diets with the synthetic glucocorticoid dexamethasone (Huang and Chuang 1999 ). Dexamethasone also decreases the steady-state level of BDK mRNA and increases the BCKDC activity state in rat hepatoma H4IIE cells (Huang and Chuang 1999 ), findings that are consistent with decreased BDK activity as a consequence of downregulation of BDK expression. No effect of the steroid is observed on the half-life of BDK mRNA, suggesting regulation at the level of gene transcription. The rat BDK gene has been cloned and 3.0 kb of its 5' upstream promoter region was previously partially characterized (Huang and Chuang 1996 , 1998 , 1999 ). A responsive element that would explain the negative effect of dexamethasone was not found within the 3.0-kb promoter region (Huang and Chuang 1999 ).

Glucocorticoids are known to stimulate gluconeogenesis. Since two of the three BCAAs (isoleucine and valine) are glucogenic, conversion of BCKDC to its activated state by downregulating BDK will provide more substrate for gluconeogenesis. Thus, the increase in serum corticosterone that occurs in starved and diabetic animals is likely an important signal for decreased BDK expression in these metabolic states.

Considering the differences in carbohydrate and protein metabolism, it is not surprising that glucocorticoids produce the opposite effect on PDC from their effect on BCKDC and expression of their respective kinases. For example, dexamethasone causes a remarkable increase in PDK4 message level in rat hepatoma cells (Huang, B., Wu, P. and Harris, R. A., unpublished results). The response is rapid, concentration dependent, blocked by the glucocorticoid receptor antagonist mifepristone and disappears rapidly upon removal of the steroid. Increased PDK expression is consistent with the need to inactivate PDC to conserve the three carbon compounds (lactate, pyruvate and alanine) for gluconeogenesis.

	Ligands for peroxisome proliferator-activated receptor (PPAR) downregulate BDK expression

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Clofibric acid has dramatic effects on the activity state of BCKDC and the activity of its kinase. Members of the fibrate family of compounds are best known for their ability to lower blood lipid levels and increase hepatic peroxisomes. However, these compounds also stimulate BCAA catabolism and cause muscle wasting (Paul and Adibi 1980 ). Although proof of cause and effect is lacking, the increase in BCAA catabolism induced by clofibric acid is proposed to limit the availability of BCAA for protein synthesis and thereby contribute to the severity of muscle wasting (Zhao et al. 1992 ). Both short- and long-term mechanisms are involved in activation of BCKDC by clofibric acid. The short-term mechanism involves direct inhibition of BDK activity by clofibric acid (Paxton and Harris 1984 ), presumably because of structural similarity to -ketoisocaproate, the naturally occurring inhibitor of the kinase. Activation of BCKDC occurs within minutes in the perfused rat heart (Paxton and Harris 1984 ) and rat skeletal muscle in vivo (Nakai, N. and Shimomura, Y., unpublished observations), observations consistent with direct inhibition of BDK by clofibric acid.

Although a long-term effect of clofibric acid on BDK expression was missed in early studies from this laboratory (Zhao et al. 1992 ), subsequent studies conducted under different conditions revealed a decrease in hepatic BDK activity, protein and message in response to the treatment of rats with clofibric acid (Paul et al. 1996 ). A reexamination in this laboratory revealed a clofibric acid–induced decrease in hepatic BDK activity in animals expressing high amounts of BDK (low protein–fed rats) but not in animals expressing low amounts of BDK (laboratory diet–fed rats) (Kobayashi, R., Nakai, N., Jaskiewicz, J. et al., unpublished results). Since clofibric acid is believed to exert many of its long-term effects by activation of PPAR, this finding suggests BDK gene expression may be regulated by this transcription factor. Thus, it would follow that other PPAR ligands may regulate BDK expression. Because fatty acids are naturally occurring PPAR ligands, the increase in free fatty acid levels occurring in starvation and diabetes may downregulate hepatic BDK expression and cause BCKDC activation in these metabolic conditions. Clofibric acid also induces large increases in PDK4 expression in several rat tissues (Wu, P. and Harris, R. A., unpublished results), suggesting naturally occurring PPAR ligands, such as fatty acids, may signal increased PDK4 gene expression. Again, this response is opposite to that of BDK, but consistent with the effects that starvation and diabetes have on the metabolism of carbohydrate and protein.

	Thyroid hormone upregulates BDK expression

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 
Hyperthyroidism induced by treatment of rats with thyroid hormone (T₃; 3,5,3'-triiodothyronine) dramatically reduces the activity state of BCKDC in the liver (Kobayashi et al. 2000 ). Hyperthyroidism also causes an increase in BDK activity, protein and message, suggesting thyroid hormone–mediated inactivation of BCKDC may result from induction of BDK. Serum BCKAs do not decrease in hyperthyroid rats, making it unlikely that changes in their mitochondrial concentration affect the activity state of BCKDC. Hyperthyroidism also has no effect on the activity state of skeletal muscle BCKDC, which normally exists predominantly in its phosphorylated and therefore inactive state. Saving BCAAs for protein synthesis in the hypercatabolic state induced by hyperthyroidism may be the primary purpose for thyroid hormone–induced inactivation of hepatic BCKDC via increased expression of BDK (Kobayashi et al. 2000 ).

The dramatic effect T₃ has on BDK expression along with the marked effects various nutritional states have on T₃ levels suggest this hormone may be particularly important in regulating the activity state of BCKDC in liver. Indeed, serum T₃ concentrations are lowered by starvation (Portnay et al. 1974 ) and diabetes (Noguchi et al. 1985 ), consistent with the observed effect (downregulation) these metabolic conditions have on BDK expression. Starvation for protein, on the other hand, increases serum T₃ concentration in the rat (Edozien et al. 1978 , Tulp et al. 1979 ), consistent with the observed upregulation of BDK expression in this nutritional state. Feeding low protein diets also increases thermogenesis (Tulp et al. 1979 ) and the expression of the mitochondrial glycerol 3-phosphate dehydrogenase (Tyzbir et al. 1981 ), two markers of the hyperthyroid state. Thus, we propose thyroid hormone is responsible for increased BDK expression in low protein–fed rats. Whether T₃ mediates this effect by either a direct or an indirect mechanism will be examined in future studies.

	FOOTNOTES

 
¹ Presented as part of the symposium "Leucine as a Nutritional Signal" given at the Experimental Biology 2000 meeting, held in San Diego, CA on April 18, 2000. This symposium was sponsored by the American Society for Nutritional Sciences and was supported by the National Institutes of Health Division of Nutritional Research Corporation and Division of Digestive Diseases and Nutrition. The proceedings of the symposium are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Susan M. Hutson, Wake Forest University School of Medicine and Robert A. Harris, Indiana University School of Medicine.

² Supported in part by grants from the National Institutes of Health Grant DK19259 (to R.A.H.), the Grace M. Showalter Trust (to R.A.H.), and a grant-in-aid for scientific research (11680024) in Japan from the Ministry of Education, Science, Sports and Culture (to Y.S.).

⁴ Abbreviations used: BCAAs, branched-chain amino acids; BCKAs, branched-chain -keto acids; BCKDC, branched-chain -keto acid dehydrogenase complex; BDK, branched-chain -keto acid dehydrogenase kinase: PDC, pyruvate dehydrogenase complex; PDK, pyruvate dehydrogenase kinase; PPAR, peroxisome proliferator-activated receptor ; T₃, 3,5,3'-triiodothyronine.

	REFERENCES

TOP ABSTRACT INTRODUCTION The branched-chain {alpha}-keto... Regulation of the branched-chain... The mitochondrial protein... Protein starvation upregulates... Starvation and diabetes... A major difference in... Glucocorticoids downregulate BDK... Ligands for peroxisome... Thyroid hormone upregulates BDK... REFERENCES

 

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