General Information:

Id: 3,503
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mus musculus
male
PPARalpha-/- mouse
article
Reference: Makowski L et al.(2009) Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation FASEB J. 23: 586-604 [PMID: 18945875]

Interaction Information:

Comment Fasting glucose and ketone levels were lower, whereas plasma NEFAs were markedly elevated in PPARalpha -/- compared to PPARalpha+/+ mice. Plasma insulin levels and the insulin:glucose ratio in PPARalpha -/-mice trended lower in the fed state but was increased relative to wild-type mice in the fasted state. Thus, the absence of PPARalpha caused an inappropriate rise in insulin secretion during fasting-induced hypoglycemia.
Formal Description
Interaction-ID: 32511

gene/protein

PPARA

affects_activity of

Drugbank entries Show/Hide entries for PPARA
Comment Fasting glucose and ketone levels were lower, whereas plasma NEFAs were markedly elevated in PPARalpha -/- compared to PPARalpha+/+ mice. Plasma insulin levels and the insulin:glucose ratio in PPARalpha -/-mice trended lower in the fed state but was increased relative to wild-type mice in the fasted state. Thus, the absence of PPARalpha caused an inappropriate rise in insulin secretion during fasting-induced hypoglycemia.
Formal Description
Interaction-ID: 32513

gene/protein

PPARA

affects_activity of

Drugbank entries Show/Hide entries for PPARA
Comment In the fed state, most fatty acid-derived acylcarnitine species were present at similar levels in wild-type compared to the knockout mice. Notable exceptions included acetylcarnitine (C2) and beta-OH-butyrylcarnitine (C4OH, a strong marker of beta-oxidation and ketone metabolism), both of which were markedly decreased in plasma, liver, and skeletal muscle of PPARalpha -/- mice regardless of feeding status. Succinylcarnitine (C4DC), which arises from the TCA cycle intermediate succinyl-CoA, was reduced in plasma and liver of PPARalpha -/-mice, independent of condition. Skeletal muscle concentrations of this metabolite were also low in PPARalpha -/- compared to wild-type mice, but only in the fasted state.
Formal Description
Interaction-ID: 32525

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Acetylcarnitine

in blood plasma, in liver, in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment In the fed state, most fatty acid-derived acylcarnitine species were present at similar levels in wild-type compared to the knockout mice. Notable exceptions included acetylcarnitine (C2) and beta-OH-butyrylcarnitine (C4OH, a strong marker of beta-oxidation and ketone metabolism), both of which were markedly decreased in plasma, liver, and skeletal muscle of PPARalpha -/- mice regardless of feeding status. Succinylcarnitine (C4DC), which arises from the TCA cycle intermediate succinyl-CoA, was reduced in plasma and liver of PPARalpha -/-mice, independent of condition. Skeletal muscle concentrations of this metabolite were also low in PPARalpha -/- compared to wild-type mice, but only in the fasted state.
Formal Description
Interaction-ID: 32542

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Hydroxybutyrylcarnitine

in blood plasma, in liver, in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment In the fed state, most fatty acid-derived acylcarnitine species were present at similar levels in wild-type compared to the knockout mice. Notable exceptions included acetylcarnitine (C2) and beta-OH-butyrylcarnitine (C4OH, a strong marker of beta-oxidation and ketone metabolism), both of which were markedly decreased in plasma, liver, and skeletal muscle of PPARalpha -/- mice regardless of feeding status. Succinylcarnitine (C4DC), which arises from the TCA cycle intermediate succinyl-CoA, was reduced in plasma and liver of PPARalpha -/-mice, independent of condition. Skeletal muscle concentrations of this metabolite were also low in PPARalpha -/- compared to wild-type mice, but only in the fasted state.
Formal Description
Interaction-ID: 32543

affects_quantity of

drug/chemical compound

Hydroxybutyrylcarnitine

Comment In the fed state, most fatty acid-derived acylcarnitine species were present at similar levels in wild-type compared to the knockout mice. Notable exceptions included acetylcarnitine (C2) and beta-OH-butyrylcarnitine (C4OH, a strong marker of beta-oxidation and ketone metabolism), both of which were markedly decreased in plasma, liver, and skeletal muscle of PPARalpha -/- mice regardless of feeding status. Succinylcarnitine (C4DC), which arises from the TCA cycle intermediate succinyl-CoA, was reduced in plasma and liver of PPARalpha -/-mice, independent of condition. Skeletal muscle concentrations of this metabolite were also low in PPARalpha -/- compared to wild-type mice, but only in the fasted state.
Formal Description
Interaction-ID: 32544

affects_quantity of

drug/chemical compound

Hydroxybutyrylcarnitine

Comment In the fed state, most fatty acid-derived acylcarnitine species were present at similar levels in wild-type compared to the knockout mice. Notable exceptions included acetylcarnitine (C2) and beta-OH-butyrylcarnitine (C4OH, a strong marker of beta-oxidation and ketone metabolism), both of which were markedly decreased in plasma, liver, and skeletal muscle of PPARalpha -/- mice regardless of feeding status. Succinylcarnitine (C4DC), which arises from the TCA cycle intermediate succinyl-CoA, was reduced in plasma and liver of PPARalpha -/-mice, independent of condition. Skeletal muscle concentrations of this metabolite were also low in PPARalpha -/- compared to wild-type mice, but only in the fasted state.
Formal Description
Interaction-ID: 32545

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Succinylcarnitine

in blood plasma, in liver, in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment In the fed state, most fatty acid-derived acylcarnitine species were present at similar levels in wild-type compared to the knockout mice. Notable exceptions included acetylcarnitine (C2) and beta-OH-butyrylcarnitine (C4OH, a strong marker of beta-oxidation and ketone metabolism), both of which were markedly decreased in plasma, liver, and skeletal muscle of PPARalpha -/- mice regardless of feeding status. Succinylcarnitine (C4DC), which arises from the TCA cycle intermediate succinyl-CoA, was reduced in plasma and liver of PPARalpha -/-mice, independent of condition. Skeletal muscle concentrations of this metabolite were also low in PPARalpha -/- compared to wild-type mice, but only in the fasted state.
Formal Description
Interaction-ID: 32547

affects_quantity of

drug/chemical compound

Succinylcarnitine

Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32548

environment

fasting

increases_activity of

Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32549

increases_quantity of

drug/chemical compound

Palmitoylcarnitine

Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32551

increases_quantity of

drug/chemical compound

Octadecenylcarnitine

Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32552

increases_quantity of

drug/chemical compound

Linoleylcarnitine

Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32553

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Linoleylcarnitine

Drugbank entries Show/Hide entries for PPARA
Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32554

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Octadecenylcarnitine

Drugbank entries Show/Hide entries for PPARA
Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32555

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Palmitoylcarnitine

Drugbank entries Show/Hide entries for PPARA
Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32557

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Octanoylcarnitine

Drugbank entries Show/Hide entries for PPARA
Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32559

gene/protein

PPARA

affects_quantity of

drug/chemical compound

O-Decanoyl-L-carnitine

Drugbank entries Show/Hide entries for PPARA
Comment In wild-type mice, fasting-induced lipolysis was accompanied by increased plasma levels of several long-chain acylcarnitine species, including C16, C18:1, and C18:2. These same metabolites were elevated an additional 2- to 3-fold in PPARalpha -/- mice. Several of the hydroxylated acylcarnitine intermediates followed a similar pattern. Likewise, in the liver of PPARalpha -/- compared to wild-type mice, fasting levels of C16 and C18:1 were elevated, but medium-chain intermediates such as C8, C10, and C12 were present at lower levels. Skeletal muscle levels of C16, C18:1, and C18:2 were also elevated in fasted PPARalpha -/- mice, whereas the medium- and shorterchain species were either unchanged or decreased relative to their wild-type counterparts. This reciprocal long- to medium/short-chain acylcarnitine profile typically reflects a metabolic block that resides distal to carnitine palmitoyltransferase 1 (CPT1), the enzyme that synthesizes long-chain acylcarnitines and that functions as the first committed step in beta-oxidation. When long-chain products of this enzyme cannot be processed efficiently they accumulate within tissues and can be subsequently exported into the general circulation.
Formal Description
Interaction-ID: 32560

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Lauroylcarnitine

Drugbank entries Show/Hide entries for PPARA
Comment Also striking was the marked skeletal muscle accumulation of isovalerylcarnitine (C5), a byproduct of leucine catabolism. Whereas fasting did not alter C5 content in skeletal muscle of wild-type mice, this metabolite increased 5-fold in PPARalpha -/- animals. Pairwise correlation analysis revealed a strong positive relation between skeletal muscle C5 levels and plasma leucine/isoleucine, but only in PPARalpha -/- animals. Surprisingly, C5 levels were not elevated in the plasma of PPARalpha -/- mice, suggesting that tissue efflux of this specific metabolite might be limited for reasons that are yet unclear.
Formal Description
Interaction-ID: 32561

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Isovalerylcarnitine

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment Also striking was the marked skeletal muscle accumulation of isovalerylcarnitine (C5), a byproduct of leucine catabolism. Whereas fasting did not alter C5 content in skeletal muscle of wild-type mice, this metabolite increased 5-fold in PPARalpha -/- animals. Pairwise correlation analysis revealed a strong positive relation between skeletal muscle C5 levels and plasma leucine/isoleucine, but only in PPARalpha -/- animals. Surprisingly, C5 levels were not elevated in the plasma of PPARalpha -/- mice, suggesting that tissue efflux of this specific metabolite might be limited for reasons that are yet unclear.
Formal Description
Interaction-ID: 32563

gene/protein

PPARA

NOT affects_quantity of

drug/chemical compound

Isovalerylcarnitine

in blood plasma
Drugbank entries Show/Hide entries for PPARA
Comment In comparison to wild-type animals, free carnitine levels were dramatically reduced in plasma, muscle, and liver of PPARalpha -/- mice; this was apparent in both the fed and fasted states.
Formal Description
Interaction-ID: 32564

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Carnitine

in blood plasma, in liver, in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment Carnitine (beta-hydroxy-gamma-trimethylammonium butyrate) is a water-soluble quaternary amine that can be obtained from dietary sources and/or synthesized endogenously from trimethylated lysine residues derived from protein degradation. Because the liver is the principal site of carnitine biosynthesis, the hepatic expression of several carnitine regulatory genes was examined. Overnight fasting decreased mRNA abundance of trimethyllysine hydroxylase, epsilon (Tmlhe) and aldehyde dehydrogenase 9 family, and member A1, (Aldh9a1) in both genotypes.
Formal Description
Interaction-ID: 32566

environment

fasting

decreases_expression of

gene/protein

TMLHE

in liver
Drugbank entries Show/Hide entries for TMLHE
Comment Carnitine (beta-hydroxy-gamma-trimethylammonium butyrate) is a water-soluble quaternary amine that can be obtained from dietary sources and/or synthesized endogenously from trimethylated lysine residues derived from protein degradation. Because the liver is the principal site of carnitine biosynthesis, the hepatic expression of several carnitine regulatory genes was examined. Overnight fasting decreased mRNA abundance of trimethyllysine hydroxylase, epsilon (Tmlhe) and aldehyde dehydrogenase 9 family, and member A1, (Aldh9a1) in both genotypes.
Formal Description
Interaction-ID: 32567

environment

fasting

decreases_expression of

gene/protein

ALDH9A1

in liver
Drugbank entries Show/Hide entries for ALDH9A1
Comment Gene expression of gammabutyrobetaine hydroxylase 1 (Bbox1), a liver-specific enzyme that catalyzes the final and rate-limiting step in carnitine synthesis, was induced 30% on fasting in PPARalpha +/+ mice but suppressed 65% in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32568

environment

fasting

increases_expression of

gene/protein

BBOX1

in liver
Drugbank entries Show/Hide entries for BBOX1
Comment Gene expression of gammabutyrobetaine hydroxylase 1 (Bbox1), a liver-specific enzyme that catalyzes the final and rate-limiting step in carnitine synthesis, was induced 30% on fasting in PPARalpha +/+ mice but suppressed 65% in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32569

gene/protein

PPARA

affects_expression of

gene/protein

BBOX1

in liver
Drugbank entries Show/Hide entries for PPARA or BBOX1
Comment In both the fed and fasted states, expression of the carnitine/organic cation transporter (OCTN2 or SLC22A5) was reduced by 40% in PPARalpha -/- compared to PPARalpha +/+ mice.
Formal Description
Interaction-ID: 32570

gene/protein

PPARA

affects_expression of

gene/protein

SLC22A5

Drugbank entries Show/Hide entries for PPARA or SLC22A5
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32571

environment

fasting

decreases_activity of

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32572

environment

fasting

increases_activity of

process

gluconeogenesis

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32573

environment

fasting

NOT affects_quantity of

drug/chemical compound

2-Oxoglutarate

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32574

environment

fasting

decreases_quantity of

drug/chemical compound

Lactate

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32575

environment

fasting

decreases_quantity of

drug/chemical compound

Pyruvate

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32576

environment

fasting

decreases_quantity of

drug/chemical compound

Citrate

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32577

environment

fasting

decreases_quantity of

drug/chemical compound

Succinate

in liver
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32578

environment

fasting

decreases_quantity of

drug/chemical compound

Fumarate

in liver
Drugbank entries Show/Hide entries for
Comment In liver of wild-type mice, the fasting-induced shift from glycolysis to gluconeogenesis was accompanied by a decrease in each of the organic acids measured, with the exception of alpha-ketoglutarate.
Formal Description
Interaction-ID: 32579

environment

fasting

decreases_quantity of

drug/chemical compound

Malate

in liver
Comment In the absence of PPARalpha, hepatic citrate levels decreased, whereas fumarate and malate increased; these changes were detected as a main effect of genotype.
Formal Description
Interaction-ID: 32581

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Citrate

in liver
Drugbank entries Show/Hide entries for PPARA
Comment In the absence of PPARalpha, hepatic citrate levels decreased, whereas fumarate and malate increased; these changes were detected as a main effect of genotype.
Formal Description
Interaction-ID: 32582

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Fumarate

in liver
Drugbank entries Show/Hide entries for PPARA or Fumarate
Comment In the absence of PPARalpha, hepatic citrate levels decreased, whereas fumarate and malate increased; these changes were detected as a main effect of genotype.
Formal Description
Interaction-ID: 32583

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Malate

in liver
Drugbank entries Show/Hide entries for PPARA
Comment A striking interaction between genotype and feeding condition was observed for alpha-ketoglutarate, which fell robustly in liver of starved PPARalpha -/- mice.
Formal Description
Interaction-ID: 32584

gene/protein

PPARA

affects_quantity of

drug/chemical compound

2-Oxoglutarate

in liver
Drugbank entries Show/Hide entries for PPARA
Comment The organic acid profile in the knockout animals is consistent with increased amino acid catabolism, as alpha-ketoglutarate functions as an amino group acceptor in multiple transamination reactions, whereas fumarate and malate are produced as intermediates of the urea cycle.
Formal Description
Interaction-ID: 32585

affects_quantity of

drug/chemical compound

2-Oxoglutarate

Comment The organic acid profile in the knockout animals is consistent with increased amino acid catabolism, as alpha-ketoglutarate functions as an amino group acceptor in multiple transamination reactions, whereas fumarate and malate are produced as intermediates of the urea cycle.
Formal Description
Interaction-ID: 32586

process

urea cycle

affects_quantity of

drug/chemical compound

Fumarate

Drugbank entries Show/Hide entries for
Comment The organic acid profile in the knockout animals is consistent with increased amino acid catabolism, as alpha-ketoglutarate functions as an amino group acceptor in multiple transamination reactions, whereas fumarate and malate are produced as intermediates of the urea cycle.
Formal Description
Interaction-ID: 32587

process

urea cycle

affects_quantity of

drug/chemical compound

Malate

Comment In skeletal muscles of wild-type mice, lactate and citrate levels fell modestly during an overnight fast, whereas concentrations of other organic acid metabolites remained stable.
Formal Description
Interaction-ID: 32588

environment

fasting

decreases_quantity of

drug/chemical compound

Lactate

in skeletal muscle
Comment In skeletal muscles of wild-type mice, lactate and citrate levels fell modestly during an overnight fast, whereas concentrations of other organic acid metabolites remained stable.
Formal Description
Interaction-ID: 32589

environment

fasting

decreases_quantity of

drug/chemical compound

Citrate

in skeletal muscle
Comment In skeletal muscles of wild-type mice, lactate and citrate levels fell modestly during an overnight fast, whereas concentrations of other organic acid metabolites remained stable.
Formal Description
Interaction-ID: 32590

environment

fasting

NOT affects_quantity of

drug/chemical compound

Pyruvate

in skeletal muscle
Comment In skeletal muscles of wild-type mice, lactate and citrate levels fell modestly during an overnight fast, whereas concentrations of other organic acid metabolites remained stable.
Formal Description
Interaction-ID: 32591

environment

fasting

NOT affects_quantity of

drug/chemical compound

Succinate

in skeletal muscle
Comment In skeletal muscles of wild-type mice, lactate and citrate levels fell modestly during an overnight fast, whereas concentrations of other organic acid metabolites remained stable.
Formal Description
Interaction-ID: 32593

environment

fasting

NOT affects_quantity of

drug/chemical compound

Fumarate

in skeletal muscle
Drugbank entries Show/Hide entries for
Comment In skeletal muscles of wild-type mice, lactate and citrate levels fell modestly during an overnight fast, whereas concentrations of other organic acid metabolites remained stable.
Formal Description
Interaction-ID: 32594

environment

fasting

NOT affects_quantity of

drug/chemical compound

Malate

in skeletal muscle
Comment Loss of PPARalpha resulted in reduced muscle levels of most organic acids. This was evident in the fed state and exacerbated by fasting, which caused a further drop in alpha-ketoglutarate, succinate, and fumarate, along with marginal declines in citrate and malate.
Formal Description
Interaction-ID: 32595

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Succinate

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment Loss of PPARalpha resulted in reduced muscle levels of most organic acids. This was evident in the fed state and exacerbated by fasting, which caused a further drop in alpha-ketoglutarate, succinate, and fumarate, along with marginal declines in citrate and malate.
Formal Description
Interaction-ID: 32596

gene/protein

PPARA

affects_quantity of

drug/chemical compound

2-Oxoglutarate

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment Loss of PPARalpha resulted in reduced muscle levels of most organic acids. This was evident in the fed state and exacerbated by fasting, which caused a further drop in alpha-ketoglutarate, succinate, and fumarate, along with marginal declines in citrate and malate.
Formal Description
Interaction-ID: 32597

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Fumarate

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA or Fumarate
Comment Loss of PPARalpha resulted in reduced muscle levels of most organic acids. This was evident in the fed state and exacerbated by fasting, which caused a further drop in alpha-ketoglutarate, succinate, and fumarate, along with marginal declines in citrate and malate.
Formal Description
Interaction-ID: 32598

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Citrate

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment Loss of PPARalpha resulted in reduced muscle levels of most organic acids. This was evident in the fed state and exacerbated by fasting, which caused a further drop in alpha-ketoglutarate, succinate, and fumarate, along with marginal declines in citrate and malate.
Formal Description
Interaction-ID: 32599

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Malate

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA
Comment Previous studies have shown that the muscle TCA cycle intermediate pool responds to changes in glucose availability and/or glycolytic activity. In agreement with these reports, fasted-state skeletal muscle content of alpha-ketoglutarate correlated strongly with blood glucose levels. Thus, the decrease in TCA cycle intermediates in muscle of the knockout mice might reflect a secondary consequence of hypoglycemia and/or glycogen depletion.
Formal Description
Interaction-ID: 32600

affects_quantity of

drug/chemical compound

2-Oxoglutarate

in skeletal muscle
Comment In plasma of wild-type mice, fasting decreased alanine and aspartate and increased the branched chain amino acids (leucine, isoleucine, and valine), whereas most other amino acids remained relatively stable.
Formal Description
Interaction-ID: 32601

environment

fasting

decreases_quantity of

drug/chemical compound

Alanine

in blood plasma
Comment In plasma of wild-type mice, fasting decreased alanine and aspartate and increased the branched chain amino acids (leucine, isoleucine, and valine), whereas most other amino acids remained relatively stable.
Formal Description
Interaction-ID: 32602

environment

fasting

decreases_quantity of

drug/chemical compound

Aspartate

in blood plasma
Comment In plasma of wild-type mice, fasting decreased alanine and aspartate and increased the branched chain amino acids (leucine, isoleucine, and valine), whereas most other amino acids remained relatively stable.
Formal Description
Interaction-ID: 32603

environment

fasting

increases_quantity of

drug/chemical compound

Leucine

in blood plasma
Comment In plasma of wild-type mice, fasting decreased alanine and aspartate and increased the branched chain amino acids (leucine, isoleucine, and valine), whereas most other amino acids remained relatively stable.
Formal Description
Interaction-ID: 32604

environment

fasting

increases_quantity of

drug/chemical compound

Isoleucine

in blood plasma
Comment In plasma of wild-type mice, fasting decreased alanine and aspartate and increased the branched chain amino acids (leucine, isoleucine, and valine), whereas most other amino acids remained relatively stable.
Formal Description
Interaction-ID: 32605

environment

fasting

increases_quantity of

drug/chemical compound

Valine

in blood plasma
Comment In PPARalpha -/- mice, fasting caused a dramatic change in 10 of the 15 plasma analytes. Most notable were robust decreases in the gluconeogenic amino acid, alanine, and the ketogenic amino acid, tyrosine.
Formal Description
Interaction-ID: 32606

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Alanine

in blood plasma
Drugbank entries Show/Hide entries for PPARA
Comment In PPARalpha -/- mice, fasting caused a dramatic change in 10 of the 15 plasma analytes. Most notable were robust decreases in the gluconeogenic amino acid, alanine, and the ketogenic amino acid, tyrosine.
Formal Description
Interaction-ID: 32607

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Tyrosine

in blood plasma
Drugbank entries Show/Hide entries for PPARA
Comment In the liver, fasting led to a marked decrease in alanine, regardless of genotype, whereas glutamate/glutamine decreased only in the PPARalpha knockout mice.
Formal Description
Interaction-ID: 32608

environment

fasting

decreases_quantity of

drug/chemical compound

Alanine

in liver
Comment In the liver, fasting led to a marked decrease in alanine, regardless of genotype, whereas glutamate/glutamine decreased only in the PPARalpha knockout mice.
Formal Description
Interaction-ID: 32609

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Glutamate

in liver
Drugbank entries Show/Hide entries for PPARA
Comment In the liver, fasting led to a marked decrease in alanine, regardless of genotype, whereas glutamate/glutamine decreased only in the PPARalpha knockout mice.
Formal Description
Interaction-ID: 32610

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Glutamine

in liver
Drugbank entries Show/Hide entries for PPARA
Comment Amino acids linked to the urea cycle (aspartate, arginine, and citrulline) were elevated in PPARalpha -/- compared to wild-type mice (detected as a main effect of genotype).
Formal Description
Interaction-ID: 32612

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Aspartate

in liver
Drugbank entries Show/Hide entries for PPARA
Comment Amino acids linked to the urea cycle (aspartate, arginine, and citrulline) were elevated in PPARalpha -/- compared to wild-type mice (detected as a main effect of genotype).
Formal Description
Interaction-ID: 32613

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Arginine

in liver
Drugbank entries Show/Hide entries for PPARA
Comment Amino acids linked to the urea cycle (aspartate, arginine, and citrulline) were elevated in PPARalpha -/- compared to wild-type mice (detected as a main effect of genotype).
Formal Description
Interaction-ID: 32614

gene/protein

PPARA

affects_quantity of

drug/chemical compound

Citrulline

in liver
Drugbank entries Show/Hide entries for PPARA
Comment Taken together, the data suggest that impaired beta-oxidation in PPARalpha -/- mice leads to a compensatory increase in amino acid catabolism.
Formal Description
Interaction-ID: 32615

gene/protein

PPARA

affects_activity of

process

incomplete fatty acid beta-oxidation

Drugbank entries Show/Hide entries for PPARA
Comment Taken together, the data suggest that impaired beta-oxidation in PPARalpha -/- mice leads to a compensatory increase in amino acid catabolism.
Formal Description
Interaction-ID: 32616

process

incomplete fatty acid beta-oxidation

increases_activity of

Comment On the basis of the pronounced C5 peak the study evaluated skeletal muscle expression of isovaleryl-CoA dehydrogenase (IVD) and HMG-CoA lyase (HMGCL), mitochondrial enzymes required for leucine catabolism to acetyl-CoA. Consistent with the metabolite profiles, a starvation-induced increase in IVD expression was observed in the PPARalpha null mice but not in the wild-type controls. HMGCL was unaffected by genotype.
Formal Description
Interaction-ID: 32617

gene/protein

PPARA

affects_expression of

gene/protein

IVD

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA or IVD
Comment On the basis of the pronounced C5 peak the study evaluated skeletal muscle expression of isovaleryl-CoA dehydrogenase (IVD) and HMG-CoA lyase (HMGCL), mitochondrial enzymes required for leucine catabolism to acetyl-CoA. Consistent with the metabolite profiles, a starvation-induced increase in IVD expression was observed in the PPARalpha null mice but not in the wild-type controls. HMGCL was unaffected by genotype.
Formal Description
Interaction-ID: 32618

gene/protein

IVD

affects_activity of

Drugbank entries Show/Hide entries for IVD
Comment On the basis of the pronounced C5 peak the study evaluated skeletal muscle expression of isovaleryl-CoA dehydrogenase (IVD) and HMG-CoA lyase (HMGCL), mitochondrial enzymes required for leucine catabolism to acetyl-CoA. Consistent with the metabolite profiles, a starvation-induced increase in IVD expression was observed in the PPARalpha null mice but not in the wild-type controls. HMGCL was unaffected by genotype.
Formal Description
Interaction-ID: 32619

gene/protein

HMGCL

affects_activity of

Drugbank entries Show/Hide entries for HMGCL
Comment On the basis of the pronounced C5 peak the study evaluated skeletal muscle expression of isovaleryl-CoA dehydrogenase (IVD) and HMG-CoA lyase (HMGCL), mitochondrial enzymes required for leucine catabolism to acetyl-CoA. Consistent with the metabolite profiles, a starvation-induced increase in IVD expression was observed in the PPARalpha null mice but not in the wild-type controls. HMGCL was unaffected by genotype.
Formal Description
Interaction-ID: 32620

gene/protein

PPARA

NOT affects_expression of

gene/protein

HMGCL

in skeletal muscle
Drugbank entries Show/Hide entries for PPARA or HMGCL
Comment The study examined hepatic transamination capacity by measuring mRNA levels of the cytosolic and mitochondrial isoforms of glutamateoxaloacetate transaminase (GOT1 and GOT2, respectively) and tyrosine aminotransferase (TAT). In wildtype mice, expression of these genes was unaffected by fasting, implying a relatively low drive for amino acid catabolism. Conversely, in PPARalpha -/- mice, overnight fasting increased hepatic mRNA levels of GOT1 and TAT 3.2- and 4.4-fold, respectively, whereas expression of the mitochondrial GOT2 mRNA was unchanged. These results fit with the known roles of the GOT1 and TAT reactions in providing amino acid-derived carbon backbones for gluconeogenesis and ketogenesis, respectively, and might explain the marked fasting-induced depletion of alpha-ketoglutarate and tyrosine in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32621

environment

fasting

NOT affects_expression of

gene/protein

GOT1

in liver
Drugbank entries Show/Hide entries for GOT1
Comment The study examined hepatic transamination capacity by measuring mRNA levels of the cytosolic and mitochondrial isoforms of glutamateoxaloacetate transaminase (GOT1 and GOT2, respectively) and tyrosine aminotransferase (TAT). In wildtype mice, expression of these genes was unaffected by fasting, implying a relatively low drive for amino acid catabolism. Conversely, in PPARalpha -/- mice, overnight fasting increased hepatic mRNA levels of GOT1 and TAT 3.2- and 4.4-fold, respectively, whereas expression of the mitochondrial GOT2 mRNA was unchanged. These results fit with the known roles of the GOT1 and TAT reactions in providing amino acid-derived carbon backbones for gluconeogenesis and ketogenesis, respectively, and might explain the marked fasting-induced depletion of alpha-ketoglutarate and tyrosine in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32622

environment

fasting

NOT affects_expression of

gene/protein

GOT2

in liver
Drugbank entries Show/Hide entries for GOT2
Comment The study examined hepatic transamination capacity by measuring mRNA levels of the cytosolic and mitochondrial isoforms of glutamateoxaloacetate transaminase (GOT1 and GOT2, respectively) and tyrosine aminotransferase (TAT). In wildtype mice, expression of these genes was unaffected by fasting, implying a relatively low drive for amino acid catabolism. Conversely, in PPARalpha -/- mice, overnight fasting increased hepatic mRNA levels of GOT1 and TAT 3.2- and 4.4-fold, respectively, whereas expression of the mitochondrial GOT2 mRNA was unchanged. These results fit with the known roles of the GOT1 and TAT reactions in providing amino acid-derived carbon backbones for gluconeogenesis and ketogenesis, respectively, and might explain the marked fasting-induced depletion of alpha-ketoglutarate and tyrosine in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32623

environment

fasting

NOT affects_expression of

gene/protein

TAT

in liver
Drugbank entries Show/Hide entries for TAT
Comment The study examined hepatic transamination capacity by measuring mRNA levels of the cytosolic and mitochondrial isoforms of glutamateoxaloacetate transaminase (GOT1 and GOT2, respectively) and tyrosine aminotransferase (TAT). In wildtype mice, expression of these genes was unaffected by fasting, implying a relatively low drive for amino acid catabolism. Conversely, in PPARalpha -/- mice, overnight fasting increased hepatic mRNA levels of GOT1 and TAT 3.2- and 4.4-fold, respectively, whereas expression of the mitochondrial GOT2 mRNA was unchanged. These results fit with the known roles of the GOT1 and TAT reactions in providing amino acid-derived carbon backbones for gluconeogenesis and ketogenesis, respectively, and might explain the marked fasting-induced depletion of alpha-ketoglutarate and tyrosine in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32624

gene/protein

PPARA

affects_expression of

gene/protein

GOT1

in liver
Drugbank entries Show/Hide entries for PPARA or GOT1
Comment The study examined hepatic transamination capacity by measuring mRNA levels of the cytosolic and mitochondrial isoforms of glutamateoxaloacetate transaminase (GOT1 and GOT2, respectively) and tyrosine aminotransferase (TAT). In wildtype mice, expression of these genes was unaffected by fasting, implying a relatively low drive for amino acid catabolism. Conversely, in PPARalpha -/- mice, overnight fasting increased hepatic mRNA levels of GOT1 and TAT 3.2- and 4.4-fold, respectively, whereas expression of the mitochondrial GOT2 mRNA was unchanged. These results fit with the known roles of the GOT1 and TAT reactions in providing amino acid-derived carbon backbones for gluconeogenesis and ketogenesis, respectively, and might explain the marked fasting-induced depletion of alpha-ketoglutarate and tyrosine in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32625

gene/protein

PPARA

affects_expression of

gene/protein

TAT

in liver
Drugbank entries Show/Hide entries for PPARA or TAT
Comment The study examined hepatic transamination capacity by measuring mRNA levels of the cytosolic and mitochondrial isoforms of glutamateoxaloacetate transaminase (GOT1 and GOT2, respectively) and tyrosine aminotransferase (TAT). In wildtype mice, expression of these genes was unaffected by fasting, implying a relatively low drive for amino acid catabolism. Conversely, in PPARalpha -/- mice, overnight fasting increased hepatic mRNA levels of GOT1 and TAT 3.2- and 4.4-fold, respectively, whereas expression of the mitochondrial GOT2 mRNA was unchanged. These results fit with the known roles of the GOT1 and TAT reactions in providing amino acid-derived carbon backbones for gluconeogenesis and ketogenesis, respectively, and might explain the marked fasting-induced depletion of alpha-ketoglutarate and tyrosine in PPARalpha -/- mice.
Formal Description
Interaction-ID: 32626

gene/protein

PPARA

NOT affects_expression of

gene/protein

GOT2

in liver
Drugbank entries Show/Hide entries for PPARA or GOT2
Comment PPARalpha -/- mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice.
Formal Description
Interaction-ID: 32627

gene/protein

PPARA

affects_activity of

Drugbank entries Show/Hide entries for PPARA
Comment PPARalpha -/- mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice.
Formal Description
Interaction-ID: 32628

environment

carnitine supplementation

affects_activity of

gene/protein

PPARA

Drugbank entries Show/Hide entries for PPARA