Wednesday, November 2, 2011

L-Carnitine Works! Yet, Maybe More Subtly Than Thought: 1.2-5g L-Carnitine Increase Expression of Genes Implicated in Fatty Acid Oxidation, Glucose & Lipid Metabolism.

Image 1: This is you... well, not exactly. It's rather an animal model of human carnitine metabolis ;-)
As a faithful student of the SuppVersity it stands out of question that you have read my masterpiece *rofl* on the "Purported Ergogenics" in the "Amino Acids for Super Humans Series". You will thusly be familiar with the inconsistency of the mostly disappointing results of randomized, placebo-controlled trials. Whether it was for fat-loss, for increases in exercise performance or whatever else the producers of respective supplements promise would happen, when you buy and take their oftentimes profoundly underdosed supplements, in the absence of pathological (or severe dietary) carnitine deficiency the observed effects, if there were any, were negligible.

A soon to be published paper by Janin Keller and other researchers from the Institute of Animal Nutrition and Nutrition Psychology at the Justus-Liebig-University, in Gießen, the Institute of Agricultural and Nutritional Sciences at the Martin-Luther-University, in Halle-Wittenberg, and the Hans-Knöll-Institute, Research Group Systems Biology/Bioinformatic, in Jena (all in Germany, btw.), does now shed some light onto the more subtle, epigenetic effects of l-carnitine supplementation (Keller. 2011).
Image 2: The calculation of human equivalent doses is a constant (unreliable) pain in my ass - either you don't have the adequate conversion ratio or you do not know how much an animal eats. weighs etc...
Note: While my calculation (see below) indicates that the equivalent dose of the dietary enrichment used in the study should be ~4-5g, Keller et al. use a different method to calculate dose equivalents that is based on the ~500g of feed the pigs consumed per day. According to their calculation the daily dose of l-carnitine on a per kg body weight base for the piglets (final body weight: 17kg) was 15mg/kg body weight l-carnitine. If we now take a look at our conversion table (cf. table 1), where this specific type of big obviously is not listed, we probably have to divide that by 1.1 to get the Human Equivalent Dose - but since this is for "Mini pigs", we will just leave it with 15mg/kg and would thus have a dose of only 1.2g for an 80kg human being.
Keller et al. fed a group of 16 male crossbred pigs (body weight at study begin: ~10kg) a standardized diet with a naturally occurring amount of <5mg/kg carnitine. Half of the pigs, did receive additional 500mg/kg carnitine in their feed. In view of the fact that this effectively centuplicated (x100) the carnitine content of the diet, and considering the fact that the average human dietary carnitine intake ranges from ~47mg in men to ~30mg in women (Lennon. 1986), this would translate into an additional dose of roughly 4-5g of supplemental l-carnitine per day for humans. If you buy your carnitine in bulk (currently ~5$ per 100g) mimicking the supplement regimen used in the study would cost you about 25cents a day... but I guess before you do that you will rightly want to know what the potential benefits would be.
Figure 1: Liver free and total l-carnitine levels (in nmol/g) in growing piglets after 21-days of normal or carnitine supplemented feed (data adapted from Keller. 2011)
As you can see in figure 1 the liver of the animals literally squirreled the l-carnitine away (this could also be the reason, why most of the previously cited studies saw only transient increases in serum l-carnitine levels and almost no increases in muscular carnitine stores). An increase of +915% in free and +937% in total liver l-carnitine content is - I probably don't have to mention that - more than significant and was not without consequences... consequences of which scientists probably would not have even thought about 10 or even 20 years ago - epigenetic changes of which Keller et al. write:
we observed that 563 genes were differentially expressed by L-carnitine. This shows that supplemental L-carnitine influences gene expression in the liver of piglets and indicates that at least some of the biological effects of L-carnitine are mediated by altering gene transcription. [...] Gene term enrichment analysis revealed that the most frequent biological processes associated with L- carnitine supplementation were dealing with metabolic processes. This was not surprising considering that the main function of L-carnitine is to stimulate energy metabolism by acting as shuttling molecule for long-chain fatty acids which also enhances the metabolic flux of glucose through the glycolytic chain. This was also confirmed by clustering analysis showing that 6 out of the 10 top-ranked clusters were dealing with metabolic processes. Representative genes from one of these clusters dealing with metabolic processes (carboxylic acid metabolic process, oxoacid metabolic process, organic acid metabolic process) encoded proteins or enzymes involved in cellular fatty acid uptake (SLC27A6, solute carrier family 27/fatty acid transporter, member 6), fatty acid activation (ACSL3, Long-chain-fatty-acid-CoA ligase 3) and fatty acid β-oxidation (ACADSB, Acyl-CoA dehydrogenase, short/branched chain specific), and most of these genes including SLC27A6, ACSL3 and ACADSB were found to be significantly up-regulated by L-carnitine supplementation.
Moreover, the researchers found that a whole host of genes (e.g. GLUT8, GCK and GPD1 more than 4x elevated) related to glucose metabolism (glucose transport, conversion of glucose into glucose 6-phosphate, and glycolysis, and hexose biosynthetic processes, like gluconeogenesis) and triglyceride metabolic and triglyceride biosynthetic processes were elevated, as well. Taken together this lead the scientists to conclude that the epigenetic changes that were induced by 21 days of (relatively) high-dose dietary l-carnitine supplementation suggest that the "conditionally essential" amino acid l-carnitine
  1. ... exerts its "well-known stimulatory effect [...] on fatty acid β-oxidation" at least partly by stimulating the transcription of genes involved in "cellular fatty acid uptake, fatty acid activation and β-oxidation"
  2. ... has profound beneficial effects on glucose metabolism and utilization, which are mediated "not only by [a genetically triggered] stimulation of glycolysis but also suppression of gluconeogenesis in the liver", and
  3. ... triggers genetic modifications which lead to an "inhibition of glycerolipid biosynthesis and stimulation of lipoprotein secretion and fatty acid catabolism", which contribute to its overall beneficial effects on lipid metabolism.
Now that you have all the facts, I'll leave it up to you to decide whether those "hidden" genetic changes are worth the 0.25$ (or 0.06$ if you use the 1.2g dose, cf. red box above) you would have to pay for your share of supplemental l-carnitine per day... and by the way: don't ask me if whatever other form of carnitine will do just as well, better or worse. This is a question only a separate study could answer!