Clarification Needed On Vitamin A And Metabolism


Dec 17, 2015

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"We recently identified PKCδ as a key component of a mitochondrial feedback loop that regulates acetyl-coenzyme A (CoA) production from pyruvate. In this pathway, PKCδ acts simultaneously as the sensor of the reduction potential of cytochrome c, reflective of the electron transfer chain (ETC) workload, and as the signal transducer that controls the pyruvate dehydrogenase complex (PDHC) activity (10). In this manner, the PKCδ pathway adjusts the fuel flux from glycolytic sources to the intensity of mitochondrial respiration, thereby controlling oxidative phosphorylation (11). The adapter protein, p66Shc, has been postulated to assemble PKCδ and cytochrome c into a signaling complex, named the PKCδ signalosome (11). In its oxidized form, cytochrome c (cytochrome c3+) oxidizes the PKCδ C1b activation domain (11, 12), leading to kinase activation (13, 14). However, the use of cytochrome c3+ as oxidant limits the electron flow from the PKCδ activation domain to the heme group of cytochrome c to a single electron at a time, although at a minimum, 1 pair needs to be moved. To facilitate the passage of electrons, PKCδ employs retinol (vitamin A alcohol) as an electron bridge (15, 16). Therefore, retinol emerged as an indispensable cofactor that modulates the activity of PKCδ and, hence, the synthesis of acetyl-CoA from pyruvate. Genetic ablation of any protein component of the PKCδ signalosome, mutations that disrupt protein or retinol-binding sites on PKCδ, as well as retinol depletion attenuate ATP synthesis and decrease oxygen consumption. In contrast, retinol supplementation enhances ATP synthesis (1012). Results from cell culture experiments indicate that cell viability is deeply compromised in the absence of vitamin A (17, 18). Furthermore, retinol supports cell survival in conditions of energy deprivation, potentially due to enhanced efficiency of fuel oxidation (19)."

"Specifically, we previously showed that the increase in ATP synthesis from pyruvate upon retinol supplementation was induced by the activation of the PKCδ signaling pathway that up-regulates the activity of PDHC in vitro and ex vivo (11). We therefore hypothesize that a persistent oversupply of retinol in vivo could alter utilization of glucose, predominantly in the major tissue sites of ATP synthesis and glucose disposal, ultimately affecting whole-body glucose metabolism. We speculate that elevated tissue levels of retinol would increase the proportion of fully assembled and functional PKCδ signalosome, thereby escalating PKCδ signaling. Chronic enforcement of pyruvate utilization would then persistently overload the ETC and consequently generate mild, but chronic, oxidative stress that would ultimately impair insulin signaling."

"Retinol-binding protein (RBP or RBP4), the sole specific carrier of retinol in the circulation, is predominantly expressed in the liver, the major tissue storage of retinoids (vitamin A and its derivatives). Hepatic retinol bound to RBP is mobilized toward the periphery of the body. Peripheral tissues, including visceral adipose, also express RBP, although to a lesser extent (20). To date, the function of extrahepatic RBP has remained elusive. Mice overexpressing human retinol-binding protein (hRBP) under the muscle creatine kinase (MCK) promoter (MCKhRBP) represent a well-established model of elevated holo- and apo-RBP levels in the circulation and retinoid concentrations in the peripheral tissues (21). Moreover, these mice have been shown to be susceptible to the development of insulin resistance. This evidence and other findings from Yang et al. (22) and Moraes-Vieira et al. (23) suggested a potential link between RBP and obesity and insulin resistance. Although a controversy remains (2426), numerous studies confirmed the correlation of increased levels of serum RBP with the magnitude of obesity and insulin resistance in humans (2730) and rodent models (22, 31,32). Two independent mechanisms have recently been proposed to account for the impairment of insulin signaling by RBP: 1) the activation of TLR4 and JNK signaling cascades by apo-RBP in resident macrophages of adipose tissue (23, 33); and 2) the activation, in muscle and adipose tissue, of the Janus kinase 2/signal transducer and activator of transcription (STAT)5 cascade upon binding of holo-RBP to its putative receptor, stimulated by retinoid acid 6. This pathway has been shown to lead to increased expression of STAT5 target genes, including suppressor of cytokine signaling 3 and peroxisome proliferator-activated receptor γ (PPARγ), which impair insulin signaling and promote lipid accumulation, respectively (34, 35)."

"PKCδ is involved in numerous signal transduction cascades and has also been implicated in the development of metabolic syndrome (MS) (36). Extensive studies from Bezy et al. (37) on the role of PKCδ in the susceptibility to insulin resistance in mice revealed a robust positive association, regardless of whether PKCδ expression was altered by genetic modifications in a tissue-specific or global manner or naturally occurred in different strains at different levels. We speculate that the proportion of the fully assembled and functional PKCδ signalosome, determined by the level of PKCδ, could be an additional factor affecting insulin sensitivity. Accordingly, inactivation of the PKCδ signaling pathway in the PKCδ knockout mouse model would contribute to the resistance to obesity-related disorders."

"In this study, we crossed MCKhRBP mice (21) with PKCδ knockout mice (38) and analyzed the resulting progeny, representing 4 distinct genotypes, for their susceptibility to the development of obesity and insulin resistance when maintained on a high-fat diet. We show that, despite the similarity of the initial phenotypes between groups with the same PKCδ genotype but different retinoid status, overexpression of hRBP significantly escalates insulin resistance upon high-fat feeding only in the presence of a functional PKCδ signalosome."

"Impairment of PKCδ improved glucose tolerance, insulin sensitivity, and led to a lean phenotype, independently of the presence of hRBP"

"Inactivation of PKCδ or p66Shc in mice results in complex metabolic phenotypes because both proteins are multifunctional. Nevertheless, PKCδ knockout andp66Shc knockout mice share a set of relevant characteristics. PKCδ-null andp66Shc-null mice display phenotypes resistant to diet-induced obesity and obesity-related disorders, even though these are linked to different alterations in lipid and glucose metabolism (37, 80, 81). Both PKCδ and p66Shc are indirect targets of insulin signaling, and both were linked to the generation of ROS in mitochondria (75, 82). Furthermore, impairment of p66Shc directly affects mitochondrial bioenergetics by increasing uncoupled respiration (80). Accordingly, the remarkable reduction of fat mass observed in p66Shc-null mice results from increased basal metabolic rate and defective adipogenesis (80). In contrast, based on the slightly reduced food intake with no alterations in feed efficiency, PKCδ-null mice likely have slower metabolic rate, even though they are also lean and display lower AF mass. In accord, increased lipid metabolism and diminished glycolysis were shown in cardiac muscle of PKCδ-null mice (83). It is noteworthy that hepatic expression levels of PKCδ were positively correlated with body mass index (37). Likewise, p66Shc levels were remarkably elevated in peripheral blood mononuclear cells of patients with type 2 diabetes (84)."

"Retinol, the nonprotein component of the PKCδ signalosome, functions as a cofactor required for the activation of PKCδ (10). We hypothesize that dietary retinol availability may be one of the signals that inhibits or stimulates the thrifty PKCδ pathway. Vitamin A is an essential nutrient that maintains the health of the body (90). Both vitamin A deficiency and excess compromise normal physiologic functions (9194). The human body is designed to efficiently prevent vitamin A toxicity by storing retinoids in high amounts, predominantly in the liver, and by maintaining homeostatic levels of retinol-RBP in the circulation (94, 95). Therefore, instances of extreme vitamin A toxicity, due to nutrient overload, are not common. Moreover, toxicity of retinol metabolites would likely lead to acute symptoms rather than chronic pathologic states. Nevertheless, in developed countries, overnutrition and increased consumption of dietary supplements may enhance the risk of excessive but subtoxic uptake of vitamin A (94). Therefore, it is important to weigh the effects of potentially elevated, even though not toxic, retinoid levels in tissues of intensive ATP synthesis. Thus, even mild oxidative stress due to up-regulation of the mitochondrial PKCδ signaling pathway may exacerbate chronic or acute pathologic conditions."

"Modifications of tissue retinoid levels via dietary vitamin A manipulation are impractical to control the PKCδ signaling pathway in experimental models. Therefore, to increase the proportion of functional PKCδ signalosome, we used theMCKhRBP mice, a unique mouse model with permanently elevated retinoid levels in the peripheral tissues (21). However, despite the marked elevation (4- to 5-fold) of muscle retinol concentrations above normal physiologic levels, we observed significant metabolic alterations in our experimental model only after 12 wk of the WD challenge."
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Feb 18, 2016
I don't do well with vitamin A in any dose, can't even take estroban, depressed mood,cold hands and feet.

Are you implying here it's not just thyroid suppressive for those sensitive?


Thread starter
Dec 17, 2015
I don't do well with vitamin A in any dose, can't even take estroban, depressed mood,cold hands and feet.

Are you implying here it's not just thyroid suppressive for those sensitive?

Synopsis: Vitamin A has a multitude of physiological actions and there is likely an ideal amount, somewhere between deficiency and excess, for optimal health and leanness. For further clarification please consult someone more knowledgeable :)


Nov 2, 2015
However, despite the marked elevation (4- to 5-fold) of muscle retinol concentrations above normal physiologic levels, we observed significant metabolic alterations in our experimental model only after 12 wk of the WD challenge."

So even with retinol concentrations 4/5 times higher than 'normal', significant metabolic alterations only occurred after 12 weeks. Doesnt seem like much to worry about unless you are overdosing on vitamin a pills or eating liver every day.


May 27, 2015
What did they feed them? I've had troubles with a, too. Increased free radicala could be from pufa, increased lipolysis and decreased glycolysis probably not good.
Mar 24, 2018
Summary, does Vitamin A for the pyruvate dehydrogenase complex have a positive or negative action? facilitate your business? thank you
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