The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Abstract

Previous findings in rats and in human vegetarians suggest that the plasma carnitine concentration and/or carnitine ingestion may influence the renal reabsorption of carnitine. We tested this hypothesis in rats with secondary carnitine deficiency following treatment with N-trimethyl-hydrazine-3-propionate (THP) for 2 weeks and rats treated with excess L-carnitine for 2 weeks. Compared to untreated control rats, treatment with THP was associated with an approximately 70% decrease in plasma carnitine and with a 74% decrease in the skeletal muscle carnitine content. In contrast, treatment with Lcarnitine increased plasma carnitine levels by 80% and the skeletal muscle carnitine content by 50%. Treatment with L-carnitine affected neither the activity of carnitine transport into isolated renal brush border membrane vesicles, nor renal mRNA expression of the carnitine transporter OCTN2. In contrast, in carnitine deficient rats, carnitine transport into isolated brush border membrane vesicles was increased 1.9-fold compared to untreated control rats. Similarly, renal mRNA expression of OCTN2 increased by a factor of 1.7 in carnitine deficient rats, whereas OCTN2 mRNA expression remained unchanged in gut, liver or skeletal muscle. Our study supports the hypothesis that a decrease in the carnitine plasma and/or glomerular filtrate concentration increases renal expression and activity of OCTN2.

Effects of single and repetitive valproic acid administration on the gene expression of placental transporters in pregnant rats: An analysis by gestational period

“…Furthermore, previous studies showed that serum carnitine levels were altered after VPA treatment (Moreno et al, 2005). Carnitine was also reported to alter Octn2 expression, which might be involved in Octn2 alteration in the present study (Schürch et al, 2010).…”

Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent

“…carnitine administration (Bartels et al 1992), which is not the case for skeletal muscle (Stephens et al 2006), this also supports the suggestion that heart tissue exhibits greater sensitivity to acute changes in plasma and tissue carnitine availability. The present observations are also consistent with the report that meldonium does not affect OCTN2 mRNA expression in mixed-fibre skeletal muscles (quadriceps femoris; Schurch et al 2010), suggesting that muscle OCTN2 transcription does not respond to acute plasma and tissue carnitine depletion, nor to increased OCTN2 substrates, such as meldonium and γ-butyrobetaine, which are elevated in the plasma as a consequence of meldonium administration (Liepinsh et al 2006;Liepinsh et al 2011b). However, under conditions of chronically reduced plasma and muscle carnitine availability, as occurs in long-standing human vegetarianism, a decline in muscle OCTN2 protein expression can be expected in humans .…”

“…The present observations are also consistent with the report that meldonium does not affect OCTN2 mRNA expression in mixed‐fibre skeletal muscles (quadriceps femoris; Schurch et al . ), suggesting that muscle OCTN2 transcription does not respond to acute plasma and tissue carnitine depletion, nor to increased OCTN2 substrates, such as meldonium and γ‐butyrobetaine, which are elevated in the plasma as a consequence of meldonium administration (Liepinsh et al . ; Liepinsh et al .…”

Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

“…In addition to the direct inhibition of CPT I or to an increase in malonyl-CoA content, a decrease in L-carnitine concentration in heart tissues was found to be one of the most effective ways to decrease the activity of CPT I. For a long time, the only non-toxic and effective compound that decreased the concentration of L-carnitine and consequently had protective effects against cardiovascular diseases was meldonium (Dambrova et al, 2002;Schurch et al, 2010). In comparison, the new compound Methyl-GBB is 10-20 times more potent as an inhibitor of BBOX and OCTN2, and it was more effective in reducing the L-carnitine concentration in blood plasma and tissues.…”