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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:761-764, April 2005

Nutrient Metabolism

Carnitine Deficiency and Supplementation Do Not Affect the Gene Expression of Carnitine Biosynthetic Enzymes in Rats1,2

Alan T. Davis3 and Thomas J. Monroe*

Departments of Surgery, Michigan State University and Spectrum Health, Grand Rapids, MI and * Department of Molecular Biology, Spectrum Health, Grand Rapids, MI

3To whom correspondence should be addressed. E-mail: davisa{at}msu.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Starved male weanling rats supplemented with 20 mmol/L pivalate in their drinking water exhibit significantly depressed concentrations of carnitine in tissues and plasma. In addition, pivalate supplementation has been linked with increased renal and hepatic trimethyllysine hydroxylase (TMLH) activity, whereas carnitine supplementation has been associated with significantly decreased hepatic {gamma}-butyrobetaine hydroxylase (BBH) activity. The purpose of this study was to determine whether pivalate or carnitine supplementation affects the activity and genetic expression of 2 enzymes of carnitine (Cn) biosynthesis, TMLH and BBH, expressed as mRNA abundance, relative to the abundance of ß-actin mRNA. Male weanling rats were administered the control treatment (C; n = 6), the pivalate treatment (P; n = 7), or the pivalate treatment plus supplemental dietary carnitine (P+Cn; n = 7). Rats in group P had elevated renal TMLH activity, relative to the other groups (P < 0.05). The groups did not differ in the abundance of renal or hepatic TMLH or BBH mRNA. A previously unreported finding was the quantifiable level of renal BBH mRNA, which was verified by direct sequencing of the BBH cDNA product amplified from kidney RNA. The groups did not differ in renal BBH mRNA abundance and renal BBH enzyme activity was not detected. Thus, the alterations in enzyme activities in the pivalate-treated rats are not regulated at the transcriptional level, and are apparently related to post-transcriptional effects on the enzymes themselves.

KEY WORDS: • carnitine • carnitine biosynthesis • trimethyllysine • {gamma}-butyrobetaine

Carnitine is a naturally occurring compound in mammalian energy metabolism. Its functions include the facilitation of long-chain fatty acid oxidation, elimination of toxic metabolites of acyl CoA excess, modulation of the free CoA to acyl CoA ratio, storage of energy as acetylcarnitine, and the intercompartmental shuttling of energy substrates (1). The first enzyme in the carnitine biosynthetic pathway, trimethyllysine hydroxylase (TMLH),4 hydroxylates trimethyllysine to 3-hydroxy-trimethyllysine, whereas the final enzyme in the pathway, {gamma}-butyrobetaine hydroxylase (BBH), hydroxylates {gamma}-butyrobetaine to carnitine. The biosynthesis of carnitine is thought to be regulated by the availability of trimethyllysine (2,3). In their review of previous studies (2–6), Vaz et al. (1) noted that the capacity of the carnitine biosynthetic pathway to generate carnitine from trimethyllysine and {gamma}-butyrobetaine far exceeds the amount of carnitine utilized.

It has been noted, however, that during starvation (7,8), clofibrate administration (9), and lactation (10), there are marked effects upon carnitine distribution and/or the efficiency of {gamma}-butyrobetaine metabolized to carnitine. In addition, thyroxine was reported to significantly increase liver carnitine concentration, as well as hepatic BBH activity (11,12). Whether these alterations in carnitine concentration are directly related to or enhanced by altered TMLH or BBH activities is unknown.

A previous study from this laboratory, using the pivalate model of secondary carnitine deficiency in rats (13), showed that TMLH activity was greater in kidney, liver, and heart of pivalate-treated rats compared with controls (14). In addition, BBH activity was depressed in rats fed a carnitine-supplemented diet relative to controls. It was unclear from these results, however, whether these effects were related to a direct effect upon the enzymes themselves, or to an alteration in the expression of the enzymes.

The purpose of the current study was to determine whether pivalate alone or in combination with supplemental carnitine alters the metabolism of trimethyllysine, via alterations in TMLH activity, expression of the TMLH mRNA, tissue concentration, and/or urinary excretion. In addition, a goal was to determine whether pivalate alone or in combination with supplemental carnitine alters the biosynthesis of carnitine, via alterations in BBH activity and expression of the BBH mRNA, as well as tissue concentration and/or urinary excretion of {gamma}-butyrobetaine and carnitine. Specifically, the working hypothesis was that the activity and mRNA expression of both enzymes would be increased in the pivalate-treated rats and decreased in the carnitine-supplemented rats relative to controls.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Animals and diets. Male weanling Sprague-Dawley rats (n = 20; Charles River) were housed individually in polycarbonate cages in a room maintained at 21 ± 2°C and 50 ± 10% humidity with a 12-h light:dark cycle. The rats were housed at the West Michigan Regional Laboratory, whose Animal Care and Use Committee approved the study. Rats were maintained in accordance with the NIH guidelines for the care and use of laboratory animals. The rats were randomly assigned to 1 of 3 groups. Control rats (group C, n = 6) were freely fed a nutritionally complete purified diet, AIN-76A [(15); Harlan Teklad]. Analysis in this laboratory determined the carnitine concentration of this diet to be 1.2 nmol/g. Rats in Group C were administered 20 mmol/L sodium bicarbonate in their drinking water, as described previously (13). Rats in the pivalate group (Group P, n = 7) were fed the same diet as the rats in Group C, and their water contained 20 mmol/L sodium pivalate. Rats in the carnitine-supplemented group (Group P+Cn, n = 7) were fed the AIN-76A diet supplemented with 0.067 mmol carnitine/g diet. This concentration of carnitine in the diet was used previously and produced 400 and 200% increases in plasma and skeletal muscle total carnitine concentration, respectively (16). Rats in Group P+Cn were administered 20 mmol/L sodium pivalate in their drinking water. The rats in all 3 groups remained in their cages and were administered these treatments for 14 d, at which time the rats were transferred to individual metabolism cages for an additional 48-h period. During this time, 24-h urinary excretions were collected (in 6 mol/L HCl), and 24-h food and fluid intake were recorded.

At the end of the study period, the rats were anesthetized with isoflurane and killed by decapitation. Blood was collected into heparinized tubes and plasma separated by centrifugation at 1500 x g for 10 min. Plasma samples were frozen at –80°C until they were analyzed. Samples of liver, skeletal muscle, heart, and kidney were obtained from each rat, and freeze-clamped in aluminum tongs cooled in liquid nitrogen. A smaller sample of liver and kidney from each rat was first submerged in RNAlater (Ambien) before freeze-clamping the tissue. The tissues remained frozen at –80°C until they were analyzed. The volume of urine was measured in a graduated cylinder, then mixed thoroughly, filtered, and an aliquot saved for further analysis.

Frozen blood, urine, liver, skeletal muscle, heart, and kidney were analyzed for carnitine and free trimethyllysine as described previously (17). TMLH activity was determined by the method of Davis (18), whereas BBH was determined by the technique of Vaz et al. (19).

    {gamma}-Butyrobetaine assay. {gamma}-Butyrobetaine samples were prepared using the technique of Janssens et al. (20), utilizing hexanoylcarnitine as the internal standard. The derivatization and analysis of the samples were conducted using the techniques of VanKempen and Odle (21) and Minkler et al. (22), as modified below. The HPLC system consisted of 2 Beckman 110B pumps (Beckman Coulter), an Alcott Chromatography Model 718 autosampler, and a FD-300 fluorescence detector (Groton Technology). A switching valve was used to switch between eluents A and B (Neptune Research). The fluorescence detector was operated with an excitation wavelength of 259 nm, an emission wavelength of 394 nm, a lamp frequency of 60 Hz, and a response time of 1 s. The analytical column was a 100 x 4.6 mm i.d. Nucleosil C8 (3 µm, 120 A) column purchased from Phenomenex.

Three eluents were used: Eluent A contained acetonitrile:water (80:20), Eluent B was 100% water, and Eluent C contained 800 mL acetonitrile, 200 mL water, 8 mL triethylamine, and 6.4 mL phosphoric acid. Initially, 100% Eluent A was pumped at a flow rate of 1.0 mL/min. At 0.2 min after sample injection, Eluent A was replaced with 100% Eluent B. From 2.9 to 3 min after injection, a linear gradient between Eluents B and C resulted in a concentration of 90% Eluent B:10% Eluent C. From 3 to 38 min after injection, a linear gradient between Eluents B and C resulted in a concentration of 48% Eluent B:52% Eluent C. From 38 to 38.1 min after injection, a linear gradient between Eluents B and C resulted in a concentration of 100% Eluent C. From 40.9 to 41 min after injection, a linear gradient between Eluents C and A resulted in a concentration of 100% Eluent A. The column was then reequilibrated for 15 min before the next injection.

    RNA isolation and PCR amplification. Expression of TMLH mRNA was determined using RT-PCR with fluorescence quantitation, using the set of primers described by Vaz et al. (23). Expression of BBH mRNA was determined using RT-PCR with fluorescence quantitation, using a set of primers described by Galland et al. (24). The expression of ß-actin was used as a control (25). TMLH, BBH, and ß-actin cDNA were amplified from 600 ng total RNA extracted from rat kidney and liver using the Superscript 1-step RT-PCR system (Invitrogen). Amplification linearity of the 3 RNA species using the same thermocycling profile and cycle number was determined empirically before quantitative experiments. The RT-PCR amplification product quantification was determined using PicoGreen (Molecular Probes) and a fluorescence microplate reader (Cytofluor series 4000, Perspective Biosystems).

    Statistics. The values shown in the text and tables are means ± SEM, except where indicated otherwise. Due to the wide range of variability for the total carnitine concentrations and for the urine {gamma}-butyrobetaine excretion, all of these values were transformed by taking the natural logarithm of the original data before analysis. The data were analyzed using 1-way ANOVA and the Fisher’s Protected Least Significant Difference (FPLSD) test. Differences were considered significant at P < 0.05. All analyses were conducted with NCSS 2004 (Number Cruncher Statistical Systems).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Carnitine and carnitine precursor concentrations in tissue and urine. Provision of pivalate in the drinking water of the Group P rats significantly decreased total carnitine in plasma and urine compared with controls (Table 1). Addition of carnitine to the diet of Group P+Cn rats significantly and markedly increased plasma and urine total carnitine relative to rats in the other 2 groups. Group P+Cn rats excreted significantly less trimethyllysine than either of the other 2 groups. Group P+Cn rats had significantly higher concentrations of {gamma}-butyrobetaine in all tissues tested, in addition to significantly higher {gamma}-butyrobetaine excretion in urine relative to rats in the other 2 groups. Group P rats had a significantly higher concentration of {gamma}-butyrobetaine in skeletal muscle than the control rats.


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  		TABLE 1 Concentrations of total carnitine, trimethyllysine, and {gamma}-butyrobetaine in plasma, liver, skeletal muscle and urine of rats in the C, P, and P+Cn groups1

 
    Renal and hepatic TMLH and BBH activities and mRNA expression. Rats in Group P had significantly higher renal TMLH activity relative to rats in the other 2 groups, which did not differ from one another (Fig. 1). Hepatic BBH activity in Group P+Cn was significantly lower than in the other 2 groups, which did not differ. The expression of renal and hepatic TMLH and BBH mRNA did not differ among the groups (Table 2; Fig. 2). Hepatic TMLH was not measured, and no renal BBH activity was detected.



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  		FIGURE 1 Renal TMLH and hepatic BBH activities in rats in the C, P, and P+Cn groups. Data are means ± SEM, n = 6 or 7. Means for an enzyme without a common different letter differ, P < 0.05.

 

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  		TABLE 2 TMLH and BBH mRNA abundance, relative to ß-actin mRNA, in liver and kidney of rats in the C, P, and P+Cn groups1

 


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  		FIGURE 2 Gel electrophoresis of hepatic and renal TMLH and BBH mRNA expression products in rats in the C, P, and P+Cn groups. Kidney: Lanes 1–10: Group C (lanes 1–3), Group P (lanes 4–7), and Group P+Cn (lanes 8–10). Liver: Lanes 11–20: Group C (lanes 11–13), Group P (lanes 14–16), and Group P+Cn (lanes 17–20).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
There has been renewed interest in carnitine biosynthesis over the past several years, primarily spurred by the characterization of several of the carnitine biosynthetic enzymes and their cDNA sequences (19,23,24,26–28). Nevertheless, as reported by Vaz and Wanders in their review of carnitine biosynthesis (1), most of the additional information tends to support the hypotheses of Davis and Hoppel (2) and Rebouche et al. (3) from the mid-1980s, who both hypothesized that carnitine biosynthesis was regulated by trimethyllysine availability. However, it was noted that alterations in the enzyme activities of TMLH and BBH occur with various alterations in diet and physiologic state. In addition, Galland et al. (12) showed alterations in both enzyme activity and expression for BBH after thyroxine administration to rats. Thus, there is an interest in determining whether these changes in enzyme activity are related to changes in enzyme expression, and whether either of these changes reflect true physiologic alterations in carnitine concentration.

In this study, 2 models known to affect carnitine metabolism were used. One model involved the addition of sodium pivalate to the drinking water, which was shown previously to cause secondary carnitine deficiency in rats (13). The second model utilized carnitine supplementation of the diet to rats given sodium pivalate in the drinking water. These modifications were specifically chosen in a previous study (14) to determine whether TMLH and BBH activities would be affected. In that previous study, it was shown that pivalate-treated rats had an almost 100% increase in TMLH activity in the kidney compared with controls, whereas the carnitine-supplemented rats had significantly decreased hepatic BBH activity.

In the current study, renal TMLH activity was significantly increased in group P rats, relative to rats in groups C or P+Cn (Fig. 1). However, hepatic BBH activity did not differ between rats in Group C and Group P. This was somewhat surprising in light of the carnitine deficiency caused by pivalate administration. Conversely, rats in group P+Cn had renal TMLH activity that did not differ from that in rats in groups C, yet they had significantly lower hepatic BBH activity than rats in Group C. These differences in activity, however, were not reflected in the hepatic or renal expression of mRNA for either of the 2 hydroxylases (Table 2).

One unexpected finding was the expression of BBH mRNA in kidney. It was demonstrated previously that rat kidney does not exhibit renal BBH activity, a finding that was repeated in the present study (data not shown). Galland et al. (24), using adult male Wistar rats, found BBH mRNA only in liver, testis, and epididymis, using ß-actin as a control. Galland et al. (27) noted that antibodies to BBH cross-reacted with proteins in the rat kidney. These proteins were 40 and 44 kDa, whereas the protein that they purified from rat liver was 43 kDa.

Vaz et al. (26) independently identified the cDNA encoding BBH using Wistar rats. However, noting the previous work concerning the tissue distribution of rat BBH activity, the researchers demonstrated the presence of mRNA expression of the enzyme only in rat liver. Concerned about the specificity of the results, the identity of the mRNA in the current study was verified by direct sequencing of the BBH cDNA product amplified from kidney RNA. Representative gels from rat kidney and rat liver are shown in Figure 2. It should be noted that all 20 kidneys tested showed a positive result for the BBH mRNA. In addition, this band was not expressed in the absence of the primers for BBH.

In conclusion, the differences in enzyme activities seen in this study were not associated with altered expression of either TMLH or BBH. Thus, the alterations in enzyme activities are not regulated at the transcriptional level and are apparently related to direct effects on the 2 enzymes. Finally, although renal BBH activity is not detectable in rats, we report for the first time the expression of BBH mRNA in rat kidney.


   ACKNOWLEDGMENTS
 
We are grateful to Laura VanWyk and Mona Wojtas for their excellent technical assistance. We also thank Sigma Tau Pharmaceuticals, Incorporated, for providing the L-carnitine.


   FOOTNOTES
 
1 Presented at Experimental Biology 03, April, 2003, San Diego, CA [Davis, A. T. & Monroe, T. J. (2003) Expression of carnitine biosynthetic enzymes is unaltered in carnitine deficient and carnitine supplemented rats (Program addendum, abstract LB403)]. Back

2 Supported by grants from the Blodgett Butterworth Health Care Foundation. Back

4 Abbreviations used: BBH, {gamma}-butyrobetaine hydroxylase; C, control rats; P, rats receiving pivalate; P+Cn, rats receiving pivalate and supplemental carnitine; TMLH, trimethyllysine hydroxylase. Back

Manuscript received 3 November 2004. Initial review completed 23 December 2004. Revision accepted 11 January 2005.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

1. Vaz, F. M. & Wanders, R.J.A. (2002) Carnitine biosynthesis in mammals. Biochem. J. 361:417-429.[Medline]

2. Davis, A. T. & Hoppel, C. L. (1986) Effect of starvation on the disposition of free and peptide-linked trimethyllysine in the rat. J. Nutr. 116:760-767.

3. Rebouche, C. J., Lehman, L. J. & Olson, L. (1986) {epsilon}-N-Trimethyllysine availability regulates the rate of carnitine biosynthesis in the growing rat. J. Nutr. 116:751-759.

4. Cederblad, G. (1976) Plasma carnitine and body composition. Clin. Chim. Acta 67:207-212.[Medline]

5. Rebouche, C. J. (1982) Sites and regulation of carnitine biosynthesis in mammals. Fed. Proc. 41:2848-2852.[Medline]

6. Rebouche, C. J. (1983) Effect of dietary carnitine isomers and {gamma}-butyrobetaine on L-carnitine biosynthesis and metabolism in the rat. J. Nutr. 113:1906-1913.

7. McGarry, J. D., Robles-Valdes, C. & Foster, D. W. (1975) Role of carnitine in hepatic ketogenesis. Proc. Natl. Acad. Sci. U.S.A. 72:4385-4388.[Abstract/Free Full Text]

8. Brass, E. P. & Hoppel, C. L. (1978) Carnitine metabolism in the fasting rat. J. Biol. Chem. 253:2688-2693.[Free Full Text]

9. Paul, H. S., Gleditsch, C. E. & Adibi, S. A. (1986) Mechanism of increased hepatic concentration of carnitine by clofibrate. Am. J. Physiol. 251:E311-E315.[Medline]

10. Robles-Valdes, C., McGarry, J. D. & Foster, D. W. (1976) Maternal-fetal carnitine relationship and neonatal ketosis in the rat. J. Biol. Chem. 251:6007-6012.[Abstract/Free Full Text]

11. Pande, S. V. & Parvin, R. (1980) Clofibrate enhancement of mitochondrial carnitine transport system of rat liver and augmentation of liver carnitine and {gamma}-butyrobetaine hydroxylase activity by thyroxine. Biochim. Biophys. Acta 617:363-370.[Medline]

12. Galland, S., Georges, B., Le Bourgne, F., Conductier, G., Viana Dias, J. & Demarquoy, J. (2002) Thyroid hormone controls carnitine status through modifications of {gamma}-butyrobetaine hydroxylase activity and gene expression. Cell. Mol. Life Sci. 59:540-545.[Medline]

13. Bianchi, P. B. & Davis, A. T. (1991) Sodium pivalate treatment reduces tissue carnitines and enhances ketosis in rats. J. Nutr. 121:2029-2036.

14. Davis, A. T. (1999) Alterations in carnitine biosynthetic enzyme activities in carnitine deficient and carnitine supplemented rats. Experimental Biology ’99, Washington, DC (Program addendum, abstract LB208) 1999.

15. American Institute of Nutrition (1987) Second report of the ad hoc committee on standards for nutritional studies. J. Nutr. 110:1726.

16. Bianchi, P. B., Lehotay, D. C. & Davis, A. T. (1996) Carnitine supplementation ameliorates the steatosis and ketosis induced by pivalate. J. Nutr. 126:2873-2879.

17. Davis, A. T. (1990) Tissue trimethyllysine biosynthesis and carnitine content in pregnant and lactating rats fed a lysine-limiting diet. J. Nutr. 120:846-856.

18. Davis, A. T. (1987) Assay of trimethyllysine hydroxylase by high performance liquid chromatography. J. Chromatogr. 422:253-256.[Medline]

19. Vaz, F. M., van Gool, S., Ofman, R., Ijlst, L. & Wanders, R.J.A. (1998) Carnitine biosynthesis: identification of the cDNA encoding human {gamma}-butyrobetaine hydroxylase. Biochem. Biophys. Res. Commun. 250:506-510.[Medline]

20. Janssens, G.P.J., De Rycke, H., Hesta, M. & De Wilde, R.O.M. (1999) Analysis of carnitine, betaine, {gamma}-butyrobetaine, and separate short-chain acylcarnitines in pigeon plasma, crop milk and tissues by HPLC coupled with UV-detection. Biotechnol. Tech. 12:231-234.

21. van Kempen, T.A.T.G. & Odle, J. (1992) Quantification of carnitine esters by high-performance liquid chromatography. Effect of feeding medium-chain triglycerides on the plasma carnitine ester profile. J. Chromatogr. 584:157-165.[Medline]

22. Minkler, P. E., Brass, E. P., Hiatt, W. R., Ingalls, S. T. & Hoppel, C. L. (1995) Quantification of carnitine, acetylcarnitine, and total carnitine in tissues by high-performance liquid chromatography: the effect of exercise on carnitine homeostasis in man. Anal. Biochem. 231:315-322.[Medline]

23. Vaz, F. M., Ofman, R., Westinga, K., Back, J. W. & Wanders, R.J.A. (2001) Molecular and biochemical characterization of rat {epsilon}-N-trimethyllysine hydroxylase, the first enzyme of carnitine biosynthesis. J. Biol. Chem. 276:33512-33517.[Abstract/Free Full Text]

24. Galland, S., Le Bourgne, F., Bouchard, F., Georges, B., Clouet, P., Grand-Jean, F. & Demarquoy, J. (1999) Molecular cloning and characterization of the cDNA encoding the rat liver gamma-butyrobetaine hydroxylase. Biochim. Biophys. Acta 1441:85-92.[Medline]

25. Raff, T., van der Giet, M., Endemann, D., Wiederholt, T. & Paul, M. (1997) Design and testing of beta-actin primers for RT-PCR that do not co-amplify processed pseudogenes. Biotechniques 23:456-460.[Medline]

26. Vaz, F. M., van Gool, S., Ofman, R., Ijlst, L. & Wanders, R.J.A. (1998) Carnitine biosynthesis. Purification of {gamma}-butyrobetaine hydroxylase from rat liver. Adv. Exp. Med. Biol. 466:117-124.

27. Galland, S., Le Bourgne, F., Gutonnet, D., Clouet, P. & Demarquoy, J. (1998) Purification and characterization of the rat liver gamma-butyrobetaine hydroxylase. Mol. Cell. Biochem. 178:163-168.[Medline]

28. Vaz, F. M., Fouchier, S. W., Ofman, R., Sommer, M. & Wanders, R.J.A. (2000) Molecular and biochemical characterization of rat {gamma}-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehyrogenase 9 in carnitine biosynthesis. J. Biol. Chem. 275:7390-7394.[Abstract/Free Full Text]




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