Effect of development and nutritional state on the uptake, metabolism and release of free and acetyl-l-carnitine by the rodent small intestine

Gross, Carol J.; Savaiano, Dennis A.

doi:10.1016/0005-2760(93)90009-x

Cited by 17 publications

(9 citation statements)

References 34 publications

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“…8b) which is endowed with biological activity per se [244,245]. Interestingly, ALC diffuses across membranes much better than LC and its efflux in the systemic circulation has been calculated to be four times greater than that of LC [245,248]. Data from AD patients have shown that after supplementation with pharmacological doses of ALC (2 g/day) for 55 days, its plasma concentrations increased from 7.2 to 10.3 lM [245].…”

Section: Natural Antioxidants Vitagenes and Neurodegenerative Disordersmentioning

confidence: 95%

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Calabrese

Cornelius

Mancuso³

et al. 2008

Neurochem Res

256

227

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The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

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Section: Natural Antioxidants Vitagenes and Neurodegenerative Disordersmentioning

confidence: 95%

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Calabrese

Cornelius

Mancuso³

et al. 2008

Neurochem Res

256

227

View full text Add to dashboard Cite

show abstract

“…3), which is endowed with biological activity per se [134, 135]. Interestingly, ALC diffuses across membranes much better than LC and its efflux in the systemic circulation has been calculated to be four times greater than that of LC [138]. Data from AD patients have shown that after supplementation with pharmacological doses of ALC (2 g/day) for 55 days, its plasma concentrations increased from 7.2 to 10.3 μM [135].…”

Section: Carnitine and Acetyl‐l‐carnitinementioning

confidence: 99%

Vitagenes, cellular stress response, and acetylcarnitine: Relevance to hormesis

et al. 2009

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Modulation of endogenous cellular defense mechanisms via the stress response signaling represents an innovative approach to therapeutic intervention in diseases causing chronic damage, such as neurodegeneration and cancer. Protein thiols play a key role in redox sensing, and regulation of cellular redox state is crucial mediator of multiple metabolic, signaling, and transcriptional processes. Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein systems. Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a low dose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response, there is now strong interest in discovering and developing pharmacological agents capable of inducing these responses. In this review we discuss the most current and up-to-date understanding of the possible signaling mechanisms by which acetylcarnitine by activating vitagenes can differentially modulate signal transduction cascades inducing apoptosis/cell death in abnormal cancer cells but at the same time enhancing defensive enzymes to protect against carcinogenesis and neurodegeneration in normal cells. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

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“…In Caco‐2 cells, this activity was located in the brush border membrane,4,5 but not in the serosal membrane 5. Extensive intracellular acetylation of carnitine (50‐60%) occurs in rat and guinea pig intestine2,3,7 and in isolated guinea pig enterocytes 7. In rat and guinea pig intestine, acetyl‐l‐carnitine is more readily released across the serosal membrane than is nonesterified carnitine 7.…”

Section: Carnitine Absorption Synthesis and Eliminationmentioning

confidence: 99%

“…Extensive intracellular acetylation of carnitine (50‐60%) occurs in rat and guinea pig intestine2,3,7 and in isolated guinea pig enterocytes 7. In rat and guinea pig intestine, acetyl‐l‐carnitine is more readily released across the serosal membrane than is nonesterified carnitine 7. Intracellular acetylation of carnitine may facilitate its diffusion across the serosal membrane 7.…”

Section: Carnitine Absorption Synthesis and Eliminationmentioning

confidence: 99%

“…In rat and guinea pig intestine, acetyl‐l‐carnitine is more readily released across the serosal membrane than is nonesterified carnitine 7. Intracellular acetylation of carnitine may facilitate its diffusion across the serosal membrane 7. In guinea pig intestine, luminal acetyl‐l‐carnitine was taken up by intestinal mucosa at about the same rate as was nonesterified carnitine, but the calculated efflux of total carnitine into the circulation was 4‐fold greater for acetyl‐l‐carnitine compared to nonesterified carnitine 7…”

Section: Carnitine Absorption Synthesis and Eliminationmentioning

confidence: 99%

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Kinetics, Pharmacokinetics, and Regulation of l‐Carnitine and Acetyl‐l‐carnitine Metabolism

Rebouche

2004

Annals of the New York Academy of Sciences

366

282

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In mammals, the carnitine pool consists of nonesterified L-carnitine and many acylcarnitine esters. Of these esters, acetyl-L-carnitine is quantitatively and functionally the most significant. Carnitine homeostasis is maintained by absorption from diet, a modest rate of synthesis, and efficient renal reabsorption. Dietary L-carnitine is absorbed by active and passive transfer across enterocyte membranes. Bioavailability of dietary L-carnitine is 54-87% and is dependent on the amount of L-carnitine in the meal. Absorption of L-carnitine dietary supplements (0.5-6 g) is primarily passive; bioavailability is 14-18% of dose. Unabsorbed L-carnitine is mostly degraded by microorganisms in the large intestine. Circulating L-carnitine is distributed to two kinetically defined compartments: one large and slow-turnover (presumably muscle), and another relatively small and rapid-turnover (presumably liver, kidney, and other tissues). At normal dietary L-carnitine intake, whole-body turnover time in humans is 38-119 h. In vitro experiments suggest that acetyl-L-carnitine is partially hydrolyzed in enterocytes during absorption. In vivo, circulating acetyl-L-carnitine concentration was increased 43% after oral acetyl-L-carnitine supplements of 2 g/day, indicating that acetyl-L-carnitine is absorbed at least partially without hydrolysis. After single-dose intravenous administration (0.5 g), acetyl-L-carnitine is rapidly, but not completely hydrolyzed, and acetyl-L-carnitine and L-carnitine concentrations return to baseline within 12 h. At normal circulating l-carnitine concentrations, renal l-carnitine reabsorption is highly efficient (90-99% of filtered load; clearance, 1-3 mL/min), but displays saturation kinetics. Thus, as circulating L-carnitine concentration increases (as after high-dose intravenous or oral administration of L-carnitine), efficiency of reabsorption decreases and clearance increases, resulting in rapid decline of circulating L-carnitine concentration to baseline. Elimination kinetics for acetyl-L-carnitine are similar to those for L-carnitine. There is evidence for renal tubular secretion of both L-carnitine and acetyl-L-carnitine. Future research should address the correlation of supplement dosage, changes and maintenance of tissue L-carnitine and acetyl-L-carnitine concentrations, and metabolic and functional changes and outcomes.

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Effect of development and nutritional state on the uptake, metabolism and release of free and acetyl-l-carnitine by the rodent small intestine

Cited by 17 publications

References 34 publications

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Vitagenes, cellular stress response, and acetylcarnitine: Relevance to hormesis

Kinetics, Pharmacokinetics, and Regulation of l‐Carnitine and Acetyl‐l‐carnitine Metabolism

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