Saturday, September 13, 2014

Creatine: Benefits Accumulate - Now it Prevents NAFLD | Reduced TG Production, Increased Efflux & Oxidation

Creatine is a dangerous steroid? Well, the study at hand shows that it will prevent not promote hepatic lipid accumulation as you will see it with many oral steroids.
As a SuppVersity reader you either take creatine or do at least know that it's the #1 proven ergogenic your money can buy! What I am pretty sure, though, is that you didn't know yet that creatine will not just make your muscles big, but also your liver clean... clean or rather free of fat.

Non-alcoholic fatty liver disease (NAFLD) has been associated with obesity and decreased insulin sensitivity. A fatty liver is considered the hepatic manifestation of the metabolic syndrome ("Liver Enzymes the #1 Marker of Insulin Resistance!?" | learn more), if creatine would effectively protect the increase in liver fat, which is the hallmark of NAFLD, it could thus eventually make the transition from the fitness community into the mainstream.
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Current data suggests that 20–30% of North Americans have NAFLD, which could progress to more severe liver damage if left untreated. If taking creatine could make them stronger and healthier (remember creatine will also improve your glucose management), the amino acid of which many doctors still believe that it was a dangerous steroid could soon make it onto their prescription lists.

Current clinical treatments for fatty liver are after all limited and so the search for safe and effective therapy is important. In vivo, phosphatidylcholine (PC) synthesis is a major consumer of hepatic methyl groups accounting for approximately 40% of all transmethylation reactions, and is an important determinant of hepatic TG metabolism. Hepatocytes have the highest activity of phosphatidyl-ethanolamineN-methyltransferase (PEMT) and they synthesize a significant portion of PC via the sequential methylation of phosphatidyl-ethanolamine (PE) - a process that relies on the methyl donor betaine which happens to have similar, albeit less pronounced ergogenic effects than cretine (learn more).
Previous rodent studies already suggested "that rats fed a creatine-supplemented high-fat diet have significantly improved glucose tolerance compared to high-fat diet fed control animals. Together these data suggest that dietary creatine influences carbohydrate metabolism as well as lipid metabolism." (da Silva. 2014).
De novo creatine biosynthesis occurs in the liver via the S--adenosylmethionine-dependent methylation of  guanidinoacetate (GAA) and is a major consumer of hepatic methyl groups, estimated to account for 40% of total methylation reactions in the body.

Suggested Read: "Supercharging Creatine With Baking Soda: Study Shows Increased Peak Power and Endurance - Plus: How Bicarbonate Could Help You Lose Fat & Build Muscle" | read more
Dietary creatine supplementation can reduce plasma GAA levels by 90% and therefore reduces demand on hepatic methylation. Previously, Jacobs & da Silva (2013) hypothesized that dietary creatine supplementation may spare AdoMet for PC synthesis, thus protecting the liver from TG accumulation. Dietary creatine supplementation prevented TG accumulation and the lowering of AdoMet in the liver of rats fed a high-fat diet (HFD).

Interestingly, dietary creatine did not alter hepatic PC levels or PEMT activity; therefore, the mechanism(s) through which creatine reduces fatty liver does not appear to be related to AdoMet availability.

In the study at hand, Silva et al. utilized the McArdle RH-7777 (McA) immortalized hepatoma cell line, 0 an established model for the study of hepatic lipid metabolism that does not express PEMT, to assess whether creatine might have a direct action on TG synthesis in liver cells.
Workout advantage!? The increased efflux of triglycerides from the liver will not just keep this vital organ "fat free", it may also be a workout advantage for endurance athletes who could use the liver fat as a substrate to fuel their muscular activity... well, it could if endurance athletes had significant amounts of liver fat. Practically speaking, however, creatine has been found to lead to a significant fall in blood glucose in endurance athletes during a standardized exercise test - albeit not to their disadvantage (Engelhardt. 1998)! A 18% increase in interval performance, is after all something many athletes would kill for.
What they observed were significant increases in PPARĪ±-activity, as they have previously reported for agents like fish oil. The increase in PPARĪ±-activity in turn triggered an increase in hepatic fatty acid oxidation and TG secretion and would thus help clear the triglycerides from the liver before they can harm you.
Figure 1: The reduced hepatic lipid accumulation in the cell study at hand is a consequence of (A) reduced
synthesis and (B) increased secretion of triglycerides (da Silva. 2014b)
The data in Figure 1 underline that this effect is mediated by decreases in hepatic lipid synthesis (A) and an increase in lipid efflux in response to being exposed to creatine. Overall, this leads to significantly reduced cellular triglyceride levels (TG; Figure 1, left).

Reduced synthesis, increased efflux, increased oxidation

Similar effects were observed for the hepatic phospholipid (PL) content, which was likewise reduced by (a) a reduced synthesis and (b) an increase efflux of PLs. But (a) and (b) are not the only factors contributing to the healthy lipid depletion.

Figure 2: Increased triglyceride oxidation, yes, increased AMPK & ACC, no (da Silva. 2014b)
As you can see in Figure 2, the provision of extra-creatine will also increase the oxidation of fatty acids (CO2 production is a measure of fatty acid oxidation), without however having similar beneficial effects on the expression of AMPK and it's fatty acid oxidating cousin ACC (see Figure 2, right) - that's in contrast to alpha-lipoic acid (learn more) and suggests that the effects are not mediated via the existing anti-oxidant effects of creatine of which you've read in "The Overlooked Non-ROS-Scavenging Antioxidant Effects of Creatine Monohydrate" (learn more)
Bottom line: The study at hand adds weight to the previously formulated hypothesis that creatine supplementation (obviously cheap, but pure creatine monohydrate) is not for muscle-headz, only.

Figure 3: Creatine monohydrate supplementation increases glucose uptake via GLUT-4 receptor expression in immobilized and active human skeletal muscle (Op't Eijnde. 2001)
On the contrary! In conjunction with the previously established anti-oxidant effects and its ability to improve glucose management via increases in AMPK and GLUT-4 (glucose receptor) expression in skeletal muscle cells (see Figure 3), the data from this recent study by scientists from the University of Alberta should eventually shut the critics, who still claim creatine was a "dangerous steroid" or at least a "gateway drug to steroid abuse" up. Unfortunately, something in the back of my head tells me that studies are less convincing to the medical orthodoxy than the glossy product flyers for the latest patentable diabesity and NAFLD drugs | Comment on Facebook!
  • da Silva, Robin, Karen Kelly, and Rene Jacobs. "Hepatic carbohydrate and lipid metabolism are altered in rats fed creatine-supplemented diets (LB151)." The FASEB Journal 28.1 Supplement (2014a): LB151.
  • da Silva, Robin P., et al. "Creatine reduces hepatic TG accumulation in hepatocytes by stimulating fatty acid oxidation." Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids (2014b). 
  • Engelhardt, Martin, et al. "Creatine supplementation in endurance sports." Medicine and Science in Sports and Exercise 30.7 (1998): 1123-1129.
  • Jacobs, Rene L., Robin da Silva, and Randy Nelson. "Creatine Supplementation may prevent NAFLD by stimulating fatty acid oxidation." The FASEB Journal 27 (2013): 222-2.
  • Op't Eijnde, B., et al. "Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization." Diabetes 50.1 (2001): 18-23.