Biosynthesis of the Essential Fatty Acid Oxidation Cofactor Carnitine Is Stimulated in Heart and Liver after a Single Bout of Exercise in Mice

Abstract

We determined whether one single bout of exercise stimulates carnitine biosynthesis and carnitine uptake in liver and heart. Free carnitine (FC) in plasma was assayed using acetyltransferase and [14C]acetyl-CoA in Swiss Webster mice after 1 hour of moderate-intensity treadmill running or 4 hours and 8 hours into recovery. Liver and heart were removed under the same conditions for measurement of carnitine biosynthesis enzymes (liver butyrobetaine hydroxylase, γ-BBH; heart trimethyllysine dioxygenase, TMLD), organic cation transporter-2 (OCTN2, carnitine transporter), and liver peroxisome proliferator-activated receptor-alpha (PPARα, transcription factor for γ-BBH and OCTN2 synthesis). In exercised mice, FC levels in plasma decreased while heart and liver OCTN2 protein expressed increased, reflecting active uptake of FC. During recovery, the rise in FC to control levels was associated with increased liver γ-BBH expression. Protein expression of PPARα was stimulated in liver after exercise and during recovery. Interestingly, heart TMLD protein was also detected after exercise. Acute exercise stimulates carnitine uptake in liver and heart. The rapid return of FC levels in plasma after exercise indicates carnitine biosynthesis by liver is stimulated to establish carnitine homeostasis. Our results suggest that exercise may benefit patients with carnitine deficiency syndromes.

The effects of L-carnitine supplementation on lipid concentrations inpatients with type 2 diabetes: A systematic review and meta-analysis of randomized clinical trials

“…Energy restriction, fasting state, and physical activity, can be associated with an elevated gene expression of OCTN2 in some tissues such as the liver and kidney; which in turn could lead to metabolism improvement. 14 , 58 Furthermore, L-carnitine reportedly enhances the efficacy of fatty acid metabolism by increasing non-oxidative glucose disposal. 59 Accordingly, L-carnitine supplementation can, conceivably, ameliorate the status of glycemic and lipid profile in patients with type 2 diabetes and metabolic syndrome.…”

Effects of Exercise Training on Renal Carnitine Biosynthesis and Uptake in the High-Fat and High-Sugar-Fed Mouse

“…Ringeis et al [17] demonstrated that 12 weeks of HF feeding with moderate intensity of ET increased PPAR-α mRNA expression in gastrocnemius muscle without producing a concomitant change in the expression of OCTN2. This is in contrast with the effects observed with acute high intensity exercise, in which increases in PPAR-α protein in kidney, liver, and heart were associated with accompanying increases in OCTN2 expression [16,17]. Similar responses were reported following 10 weeks of twice daily treadmill running in rat kidney and liver [14].…”

“…PPARα is a ligand-activated transcription factor that stimulates hepatic and renal gene expression of γ-BBH, OCTN2, and carnitine palmitoyltransferase-I (CPT-1) to enhance mitochondrial FA oxidation [8,9,12,13]. We have shown that expression of γ-BBH and OCTN2 is increased in rat and mouse tissue in response to acute and chronic exercise training (ET), with both conditions stimulating carnitine biosynthesis and increasing the levels of plasma carnitine [14][15][16].…”

Effects of an early life diet containing large phospholipid-coated lipid globules on hepatic lipid metabolism in mice

“…Hepatic carnitine can be obtained from the diet, can be locally biosynthesized, or can originate from tissue redistribution. Carnitine biosynthesis is higher in conditions in which rates of β-oxidation are chronically elevated 39,40 . Negligible accumulation of (long-chain) acylcarnitine species, seen in the livers of both cIMF and eIMF-fed mice, implies that β-oxidation does not outpace the TCA cycle in this tissue 29,41 .…”

“…Higher protein levels of TCA cycle enzymes may correspond with a higher TCA cycle flux. The concomitant higher levels of proteins involved in β-oxidation 38 and the higher hepatic carnitine concentration are suggestive of higher β-oxidation activity 39,40 . An increased flux through the β-oxidation cycle, also yielding more acetyl-CoA, would then require a higher flux through the TCA cycle.…”