Nutrients In The Shadow-nutrients Of Substance (Lipoic Acid)

[Terma]

https://www.ias.ac.in/article/fulltext/jbsc/006/04/0459-0474

Lipoic acid (figure 1) has long been recognised as a vital cofactor in the enzyme complexes that catalyse the oxidative decarboxylation of α-keto acids such as pyruvic, α-ketoglutaric and branched chain α-keto acids formed during the catabolism of branched chain amino acids. Recently the decarboxylation of glycine has been shown to require lipoic acid (Fujiwara et al., 1979). A dietary requirement for lipoic acid in animals has not been established, nor has a systematic estimation of the lipoic acid content in animals during ageing been done. The coenzymic role of lipoic acid in transacylation reactions involved in the oxidation of pyruvate is presented in figure 1.

Pyruvate is at the centre of metabolic disposition of substrates from the utilisation of proteins and carbohydrates and pyruvic dehydrogenase (PD) (EC 1.2.4.1) is crucial for the complete oxidation of glucose and for lipid biosynthesis from glucose (Jungas, 1970,1971; Halperin, 1970). PD exists in a catalytically active (dephosphorylated) and an inactive (phosphorylated) form. Though the content of PD is the same in normal and diabetic livers, a larger proportion of the enzyme is in its inactive state in streptozotocin induced diabetes in rats (Weinberg and Utter, 1980). Similar reductions in active PD has been, reported in perfus ed rat heart in alloxan diabetes (Kerbey et al., 1976). Administration of insulin restored the PD activity to normal levels (Hughes et al., 1980). We have found that administration of lipoic acid, like insulin treatment increases PD activity in the livers of both no rmal and diabetic rats (table 1). From table 2 it can be seen that blood pyruvate levels in alloxan diabetic rats are about 60% higher than normal and administration of lipoic acid reduces the elevated blood pyruvate in diabetic rats to near normal values in 60 min. We have previously shown that biochemical abnormalities such as hyp oglycemia, ketonemia, reduction in liver glycogen and impaired incorporation of 2- [ 14 C] -acetate into fatty acids in alloxan diabetic rats were brought to near normal levels by the oral or intraperitoneal administration of lipoic or dihydrolipoic acid (Natraj et al., 1984). Lipoic acid content in diabetic livers is markedly reduced as compared to its amount in normal liver (Natraj et al., 1984).

It has been proposed that the increased oxidation of fatty acids generates excess AcCoA and acetoacetyl CoA (AcAcCoA) which acylate the lipoic acid residues of PD. Acylated lipoic acid has been shown to activate PD kinase and thus bring about inhibition of PD (Cate and Roche, 1979). The respective metabolic roles of PD and PC in various organs are illustrated in table 3. It will be seen from the table that PC is crucial for gluconeogenesis, whereas PD is e ssential for energy production. In diabetes, the energy production occurs through the oxidation of fatty acids, and it is well recognised that the respiratory quotient is low due to abnormal fatty acid oxidation (Randle, 1976). In gluconeogenic organs such as the kidney, PC > PD, but in energy consuming organs like the heart PD > PC. Wh ereas in the normal liver PD and PC are finely balanced, in the diabetic liver PC > PD due to the increased demand for glucose (Randle et al., 1977).

A decreased glucose tolerance is common in a majority of people during ageing. The diminution in the levels of lipoic acid in the liv er of diabetic rats and the effectiveness of dietary lipoic acid in restoring most of the biochemical abnormalities in diabetes led us to consider whether the biosynthesis of li poic acid is impaired during ageing/diabetes. Though lipoic acid is a ubiquitous component in all aerobic organisms and animals, most tissues and microorganisms contain only minute quantities of this material. Lipoic acid is biosynthesized in Escherichia coli from octanoic acid, hydroxy octanoic acid and more efficiently fr om thiooctanoic acid (White, 1980a,b; 1981). Carreau et al. (1977) have shown that linoleic acid and to a smaller extent oleic acid, act as precursors for lipoic acid biosynthesis in the rat. Further, the subcellular location of lipoic acid biosynthesis has been shown to be the microsomal fraction in rat liver (Spoto et al., 1982). However, as shown in table 4, in animal tissues arachidonic acid appears to be the most immediate precursor followed by linoleic acid, though octanoic acid incorporated into lipoic acid is unlikely to be of physiological significance in view of the unlikely occurrence of free octanoic acid in body metabolism. The scheme of biosynthesis of lipoic acid from arachidonic acid is given in figure 3.

Further, methionine and cysteine have been shown to be equally effective as sulphur donors in the biosynthesis of lipoic acid (Dupre et al., 1980). We have confirmed this finding in experiments with diabetic rats. We have further demonstrated that the biosynthesis of lipoic acid from linoleic acid is impaired in diabetes and administration of insulin enhances this conversion (table 5).

Essential fatty acids have an insulin sparing effect in diabetes (Houtsmuller et al., 1981). Is this effect due to an increased biosynthesis of lipoic acid from linoleic acid?

Octanoic (caprylic) acid aside, I've never heard of arachidonic acid suggested as a precursor for lipoic acid and I wonder if that might be true in humans. They are curiously related other ways: alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis. - PubMed - NCBI

I forgot to mention in the other thread that you can conceivably get issues from supplementing glycine during a lipoic acid deficiency (especially in kidney).

If anyone knows more about this relationship it might save me a lot of time especially if it's different in humans. This is older research.

Bolded @Amazoniac-style.

 

[SB4]

@Terma Interesting about AA and LA being a precursor to ALA. Have you tried ALA? I didn't notice any increased tolerance to carbs with it but I have fished out an old bottle of it and will start it up again regardless.

 

[Terma]

I got significant effects from large doses of R-ALA 600mg+ (1200mg ALA) but it has such short half-life and burns my throat without capsules. Don't know what its shelf life is either.

I assumed that the caprylic acid also contributes to lipoic synthesis a bit, and curiously at one point R-ALA felt subjectively similar to caprylic acid, even though I assume there must be limited synthesis and I assumed R-ALA was having a pharmacological effect (rather than fixing deficiency).

I'm really not sure about o-6 being a precursor to it. But it would seem critical so it would be good to find out if it's true or not in humans.