Paola Benatti

Polyunsaturated fatty acids: Biochemical, nutritional and epigenetic properties

Dietary polyunsaturated fatty acids (PUFA) have effects on diverse physiological processes impacting normal health and chronic diseases, such as the regulation of plasma lipid levels, cardiovascular and immune function, insulin action and neuronal development and visual function. Ingestion of PUFA will lead to their distribution to virtually every cell in the body with effects on membrane composition and function, eicosanoid synthesis, cellular signaling and regulation of gene expression. Cell specific lipid metabolism, as well as the expression of fatty acid-regulated transcription factors, likely play an important role in determining how cells respond to changes in PUFA composition. This review will focus on recent advances on the essentiality of these molecules and on their interplay in cell physiology, leading to new perspective in different therapeutic fields.

Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system.

An efficient regulation of fuel metabolism in response to internal and environmental stimuli is a vital task that requires an intact carnitine system. The carnitine system, comprehensive of carnitine, its derivatives, and proteins involved in its transformation and transport, is indispensable for glucose and lipid metabolism in cells. Two major functions have been identified for the carnitine system: (1) to facilitate entry of long‐chain fatty acids into mitochondria for their utilization in energy‐generating processes; (2) to facilitate removal from mitochondria of short‐chain and medium‐chain fatty acids that accumulate as a result of normal and abnormal metabolism. In cancer patients, abnormalities of tumor tissue as well as nontumor tissue metabolism have been observed. Such abnormalities are supposed to contribute to deterioration of clinical status of patients, or might induce cancerogenesis by themselves. The carnitine system appears abnormally expressed both in tumor tissue, in such a way as to greatly reduce fatty acid beta‐oxidation, and in nontumor tissue. In this view, the study of the carnitine system represents a tool to understand the molecular basis underlying the metabolism in normal and cancer cells. Some important anticancer drugs contribute to dysfunction of the carnitine system in nontumor tissues, which is reversed by carnitine treatment, without affecting anticancer therapeutic efficacy. In conclusion, a more complex approach to mechanisms that underlie tumor growth, which takes into account the altered metabolic pathways in cancer disease, could represent a challenge for the future of cancer research. J. Cell. Physiol. 182:339–350, 2000.

Carnitine: an osmolyte that plays a metabolic role.

Carnitine, gamma‐trimethyl‐beta‐hydroxybutyrobetaine, is a small molecule widely present in all cells from prokaryotic to eukaryotic ones. It is the sole source of carbon and nitrogen in some bacteria; it serves as osmoprotectant in others. It is a carrier of acyl moieties, and exclusively of long‐chain fatty acids for mitochondrial beta‐oxidation in mammals. The conspicuously similar composition of the intracellular milieu among widely different species in relation to organic osmolyte systems involves the methylamine family to which carnitine belongs. This prompted us to examine the osmolytic properties of carnitine in an attempt to clarify the metabolic functions carnitine has acquired during evolution. An understanding of the metabolic functions of this organic compatible solute impinge on research involving this compound. J. Cell. Biochem. 80:1–10, 2000.

Systemic and Brain Metabolic Dysfunction as a New Paradigm for Approaching Alzheimer’s Dementia

Since its definition Alzheimer’s disease has been at the centre of consideration for neurologists, psychiatrists, and pathologists. With John P. Blass it has been disclosed a different approach Alzheimer’s disease neurodegeneration understanding not only by the means of neurochemistry but also biochemistry opening new scenarios in the direction of a metabolic system degeneration. Nowadays, the understanding of the role of cholesterol, insulin, and adipokines among the others in Alzheimer’s disease etiopathogenesis is clarifying approaches valuable not only in preventing the disease but also for its therapy.

CARNITINE REPLACEMENT IN END-STAGE RENAL DISEASE AND HEMODIALYSIS

Abstract: In patients with chronic renal failure, not yet undergoing hemodialysis (HD), plasma acylcarnitines accumulate in part due to a decreased renal clearance of esterified carnitine moieties. In these patients, a high acylcarnitine/free‐carnitine ratio is usually found in plasma. Patients undergoing maintenance HD, usually present with plasma carnitine insufficiency, due to accumulation of metabolic intermediates combined with impaired carnitine biosynthesis, reduced protein intake and increased removal via HD. Plasma carnitine concentrations rapidly decrease to 40% of baseline level during the dialysis session, with a slow restoration of the carnitine concentration during the interdialytic period, mainly from organs of storage (skeletal muscle). Dietary intake also plays an important role in carnitine homeostasis of HD patients since the prevalence of malnutrition ranges from 18% to 75% of these cases. This could differentially affect various body compartments, with clinical consequences such as impaired muscle function, decreased wound healing, altered ventilatory response, and abnormal immune function. Repeated hemodialytic treatments are associated with decreased carnitine stores in skeletal muscle. The administration of intravenous l‐carnitine (LC) postdialysis replenishes the free carnitine removed from the blood and contributes to replenishment of muscle carnitine content. LC supplementation in selected uremic patients may yield clinical benefits by ameliorating several conditions, such as erythropoietin‐resistant anemia, decreased cardiac performance, intradialytic hypotension, muscle symptoms, as well as impaired exercise and functional capacities. Furthermore, LC may positively influence the nutritional status of HD patients by promoting a positive protein balance, and by reducing insulin resistance and chronic inflammation, possibly through an effect on leptin resistance.

The carnitine system and body composition.

Abstract.Carnitine is a trimethylamine molecule that plays a unique role in cell energy metabolism. Mitochondrial betaoxidation of long-chain fatty acids, the major process by which fatty acids are oxidized, is ubiquitously dependent on carnitine. Control of mitochondrial beta-oxidation through carnitine adapts to differing requirements in different tissues. The physiological role of carnitine and its system in body composition is understood from insights into skeletal muscle metabolism, which converge into the metabolic heterogeneity of muscle fibers, and contractile properties that are correlated with phenotypes of resistance to fatigue. In skeletal muscle, the importance of the function of the carnitine system in the control and regulation of fuel partitioning not only relates to the metabolism of fatty acids and the capacity for fatty acid utilization, but also to systemic fat balance and insulin resistance. The carnitine system is shown to be determinant in insulin regulation of fat and glucose metabolic rate in skeletal muscle, this being critical in determining body composition and relevant raised levels of risk factors for cardiovascular disease, obesity, hypertension, and type 2 diabetes.

Acetyl-L-carnitine protects striatal neurons against in vitro ischemia: the role of endogenous acetylcholine.

The neuronal death after ischemia is closely linked to the essential role of mitochondrial metabolism. Inhibition of mitochondrial respiratory chain reduces ATP generation leading to a dysregulation of ion metabolism. Acetyl-L-carnitine (ALC) influences the maintenance of key mitochondrial proteins for maximum energy production and it may play a neuroprotective role in some pathological conditions. In this study we have analyzed ALC-mediated neuroprotection on an in vitro model of brain ischemia. Field potential recordings were obtained from a rat corticostriatal slice preparation. In vitro ischemia (oxygen and glucose deprivation) was delivered by switching to a solution in which glucose was omitted and oxygen was replaced with N2. Ten minutes of in vitro ischemia caused an irreversible loss of the field potential amplitude. Pretreatment with ALC produced a progressive and dose-dependent recovery of the field potential amplitude following in vitro ischemia. The neuroprotective effect of ALC was stereospecific since the pretreatment with two different carnitine-related compounds did not cause neuroprotection. The choline transporter inhibitor hemicholinium-3 blocked the neuroprotective effect of ALC. ALC-mediated neuroprotection was also prevented either by the non-selective muscarinic antagonist scopolamine, or by the putative M2-like receptor antagonist methoctramine. Conversely, the effect of ALC was not altered by the M1-like receptor antagonist pirenzepine. These findings show that ALC exert a neuroprotective action against in vitro ischemia. This neuroprotective effect requires the activity of choline uptake system and the activation of M2 muscarinic receptors.

Acetyl-l-carnitine increases artemin level and prevents neurotrophic factor alterations during neuropathy

Damages to the nervous system are the primarily cause of neuropathy and chronic pain. Current pharmacological treatments for neuropathic pain are not able to prevent or revert morphological and molecular consequences of tissue injury. On the other hand, many neurotrophins, like nerve growth factor (NGF), paired off restorative effects with hyperalgesia. Interestingly, the glial cell line-derived neurotrophic factors GDNF and Artemin (ARTN) seem to support neuron survival and to normalize abnormal pain behaviour. In the present research protein levels of NGF, GDNF and ARTN were evaluated in a rat model of peripheral neuropathy, the chronic constriction injury (CCI). NGF was increased by CCI in the ipsilateral dorsal root ganglia (DRG), in the spinal cord and in the periaqueductal grey matter (PAG). On the contrary, ARTN was decreased bilaterally in DRG, spinal cord and PAG. GDNF levels decreased in ipsilateral DRG, whereas the constriction did not modify its expression in the central nervous system districts. Repeated treatments with the antihyperalgesic and neuroregenerative compound acetyl-l-carnitine (ALCAR; 100 mgkg(-1) i.p. twice daily for 15 days) was able to prevent the increase of NGF levels. In conditions of pain relief ALCAR normalized peripheral and central alterations of GDNF and ARTN levels. Characteristically, sham animals that underwent the same ALCAR treatment, showed increased levels of ARTN both in the DRG and in the spinal cord. These data offer a new point of view on the mechanism of the antihyperalgesic as well as the neuroprotective effect of ALCAR.

Carnitine System and Tumor

Carnitine, a name derived from the Latin carnis (flesh), was isolated from meat extracts in 19051 and early its chemical formula (C7H15NO3) was proposed. Its structure, a trimethylbetaine of γ-amino-β-hydroxybutyric acid, was correctly identified and published about twenty years later.2 Initially, some circumstances led to consider carnitine as a vitamin. By about 1945, all of the important vitamins of the B group had been identified, but the interest in the discovery of still missing B-vitamins, their lack being possibly correlated with anemia, was tremendous. In those years Fraenkel and coworkers observed that the mealworm Tenebrio molitor required for normal growth and survival, in addition to at least eight of the known B-vitamins, also folic acid and a new factor contained in brewers yeast or in liver extract, which they tentatively named vitamin-BT (T for Tenebrio).3 The unfavorable properties of this factor (it was hygroscopic and extremely water soluble, thus, hard to crystallize) made its isolation difficult but, finally, the missing vitamin-BT was identified as carnitine.4 The widespread distribution of carnitine was established in microorganisms, lower animals, and in all organs of mammals, and in plants too.5