Modulation of Δ5- and Δ6-desaturases in the brain-liver axis.

Objective: Obesity is associated with liver depletion of ω-3 polyunsaturated fatty acids (ω-3 PUFAS) promoting steatosis and inflammation, whose levels are maintained by diet or biosynthesis involving Δ-5D, Δ-6D desaturases and elongases.

Method: We aimed to assess Δ-5D and Δ-6D activities in liver and brain from mice fed a control diet (CD) or high-fat diet (HFD) for four to sixteen weeks.

Results: HFD led to (1) an early (4 weeks) enhancement in liver Δ-5D, Δ-6D, and PPAR-α activities, without changes in oxidative stress, liver damage or fat accumulation; (2) a latter progressive loss in hepatic desaturation with insufficient compensatory increases in mRNA and protein expression, leading to ω-3 PUFA depletion, PPAR-α down-regulation reducing FA oxidation, and liver steatosis with enhancement in lipogenesis; and (3) brain ω-3 PUFA depletion after 12 to 16 weeks of HFD feeding.

Relevant Aspects of Combined Protocols for Prevention of N(M)AFLD and Other Non-Communicable Diseases.

Obesity is a global health issue characterized by the excessive fat accumulation, leading to an increased risk of chronic noncommunicable diseases (NCDs), including metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, there are no approved pharmacological protocols for prevention/treatment of MAFLD, and due the complexity lying beneath these mechanisms, monotherapies are unlikely to be efficacious. This review article analyzes the possibility that NCDs can be prevented or attenuated by the combination of bioactive substances, as they could promote higher response rates, maximum reaction results, additive or synergistic effects due to compounds having similar or different mechanisms of action and/or refraining possible side effects, related to the use of lower doses and exposures times than monotherapies.

Omega-3 Lipid Mediators: Modulation of the M1/M2 Macrophage Phenotype and Its Protective Role in Chronic Liver Diseases.

The complex interplay between dietary factors, inflammation, and macrophage polarization is pivotal in the pathogenesis and progression of chronic liver diseases (CLDs). Omega-3 fatty acids (FAs) have brought in attention due to their potential to modulate inflammation and exert protective effects in various pathological conditions. Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise in mitigating inflammation and enhancing the resolution of inflammatory responses.

Potential Clinical Applications of Pro-Resolving Lipids Mediators from Docosahexaenoic Acid.

Docosahexaenoic acid (C22:6-3, DHA) is the precursor of specialized pro-resolving lipid mediators (SPMs), such as resolvin, protectin, and maresin families which have been considered therapeutic bioactive compounds for human health. Growing evidence indicates that DHA and SPMs are beneficial strategies in the amelioration, regulation, and duration of inflammatory processes through different biological actions. The present review discusses the reported therapeutic benefits of SPMs on various diseases and their potential clinical applications.

Protein concentrations and activities of fatty acid desaturase and elongase enzymes in liver, brain, testicle, and kidney from mice: Substrate dependency.

The synthesis rates of n-3 and n-6 polyunsaturated fatty acids (PUFAs) in rodents and humans are not agreed upon and depend on substrate availability independently of the capacity for synthesis. Therefore, we aimed to assess the activities of the enzymes for n-3 and n-6 PUFA synthesis pathways in liver, brain, testicle, kidney, heart, and lung, in relation to their protein concentration levels. Eight-week-old Balb/c mice (n = 8) were fed a standard chow diet (6.

Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet.

Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)'s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM.

Cellular Functional, Protective or Damaging Responses Associated with Different Redox Imbalance Intensities: A Comprehensive Review.

Reactive species (RS) are produced in aerobic and anaerobic cells at different concentrations and exposure times, which may trigger diverse responses depending on the cellular antioxidant potential and defensive devices. Study searches were carried out using the PubMed database of the National Library of Medicine-National Institutes of Health. Cellular RS include reactive oxygen (ROS), nitrogen (RNS), lipid (RLS) and electrophilic species that determine either cell homeostasis or dysfunctional biomolecules.

Influence of the nutritional status and oxidative stress in the desaturation and elongation of n-3 and n-6 polyunsaturated fatty acids: Impact on non-alcoholic fatty liver disease.

Polyunsaturated fatty acids (PUFA) play essential roles in cell membrane structure and physiological processes including signal transduction, cellular metabolism and tissue homeostasis to combat diseases. PUFA are either consumed from food or synthesized by enzymatic desaturation, elongation and peroxisomal β-oxidation. The nutritionally essential precursors α-linolenic acid (C18:3n-3; ALA) and linoleic acid (C18:2n-6; LA) are subjected to desaturation by Δ6D/Δ5D desaturases and elongation by elongases 2/5, enzymes that are induced by insulin and repressed by PUFA.

N-3 PUFAs and their specialized pro-resolving lipid mediators on airway inflammatory response: beneficial effects in the prevention and treatment of respiratory diseases.

Respiratory diseases include a wide range of pathologies with different clinical manifestations, affecting the normal airways and lung function. An increase in the inflammatory response is considered a characteristic hallmark of these diseases, being also a critical factor for their progression. The n-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid (C20:4n-3, EPA), docosahexaenoic acid (C22:6n-3, DHA) and their lipid mediators are known to have an inflammation pro-resolution effect.

Standpoints in mitochondrial dysfunction: Underlying mechanisms in search of therapeutic strategies.

Mitochondrial dysfunction has been defined as a reduced efficiency of mitochondria to produce ATP given by a loss of mitochondrial membrane potential, alterations in the electron transport chain (ETC) function, with increase in reactive oxygen species (ROS) generation and decrease in oxygen consumption. During the last decades, mitochondrial dysfunction has been the focus of many researchers as a convergent point for the pathophysiology of several diseases. Numerous investigations have demonstrated that mitochondrial dysfunction is detrimental to cells, tissues and organisms, nevertheless, dysfunctional mitochondria can signal in a particular way in response to stress, a characteristic that may be useful to search for new therapeutic strategies with a common feature.

Perspectives in liver redox imbalance: Toxicological and pharmacological aspects underlying iron overloading, nonalcoholic fatty liver disease, and thyroid hormone action.

Oxidative stress is an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control, and/or molecular damage altering cellular functions. This redox imbalance may trigger different responses depending on the antioxidant potential of a given cell, the level of reactive oxygen/nitrogen species (ROS/RNS) attained and the time of exposure, with protective effects being induced at low ROS/RNS levels in acute or short-term conditions, and harmful effects after high ROS/RNS exposure in prolonged situations. Relevant conditions underlying liver redox imbalance include iron overload associated with ROS production via Fenton chemistry and the magnitude of the iron labile pool achieved, with low iron exposure inducing protective effects related to nuclear factor-κB, signal transducer and activation of transcription 3, and nuclear factor erythroid-related factor 2 (Nrf2) activation and upregulation of ferritin, hepcidin, acute-phase response and antioxidant components, whereas high iron exposure causes drastic oxidation of biomolecules, mitochondrial dysfunction, and cell death due to necrosis, apoptosis and/or ferroptosis.

N-3 Polyunsaturated Fatty Acids and Their Lipid Mediators as A Potential Immune-Nutritional Intervention: A Molecular and Clinical View in Hepatic Disease and Other Non-Communicable Illnesses.

In recent years, the beneficial effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) intake on human health has been widely accepted in the field of immunonutrition. Today, we find a diversity of supplements based on n-3 PUFAs and/or minerals, vitamins and other substances. The main objective of this review is to discuss the importance of n-3 PUFAs and their derivatives on immunity and inflammatory status related to liver disease and other non-communicable illnesses.

Effects of acute iron overload on Nrf2-related glutathione metabolism in rat brain.

Iron (Fe) overload triggers free radical production and lipid peroxidation processes that may lead to cell death (ferroptosis). The hypothesis of this work was that acute Fe-dextran treatment triggers Nrf2-mediated antioxidant regulation in rat brain involving glutathione (GSH) metabolism. Over the initial 8 h after Fe-dextran administration (single dose of 500 mg Fe-dextran/kg), total Fe, malondialdehyde (MDA) content, glutathione peroxidase (GPx), GPx-Se dependent (GPx-Se) and glutathione S-transferases (GST) activities were increased in rat whole brain.

Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development of an excessive inflammatory response. Liver resident cells and those recruited in response to injury generate pro-inflammatory signals such as reactive oxygen species, cytokines, chemokines, proteases and lipid mediators that contribute to hepatocellular necrosis and apoptosis. Besides, dying hepatocytes release damage-associated molecular patterns that actívate inflammasomes to further stimulate inflammatory responses leading to massive cell death.

Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease.

Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPR) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways.

The metabolic dysfunction of white adipose tissue induced in mice by a high-fat diet is abrogated by co-administration of docosahexaenoic acid and hydroxytyrosol.

Background: Nutritional interventions are promising tools for the prevention of obesity. The n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) docosahexaenoic acid (DHA) modulates immune and metabolic responses while the antioxidant hydroxytyrosol (HT) prevents oxidative stress (OS) in white adipose tissue (WAT).

Objective: The DHA plus HT combined protocol prevents WAT alterations induced by a high-fat diet in mice.

Protective Effects of Eicosapentaenoic Acid Plus Hydroxytyrosol Supplementation Against White Adipose Tissue Abnormalities in Mice Fed a High-Fat Diet.

Objective: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations.

Methods: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks.

Suppression of high-fat diet-induced obesity-associated liver mitochondrial dysfunction by docosahexaenoic acid and hydroxytyrosol co-administration.

Objective: Obesity-induced by high-fat diet (HFD) is associated with liver steatosis, oxidative stress and mitochondrial dysfunction, which can be eluded by the co-administration of the lipid metabolism modulator docosahexaenoic acid (DHA) and the antioxidant hydroxytyrosol (HT).

Methods: C57BL/6J mice fed a HFD were orally administered either with vehicle, DHA, HT or DHA+HT for 12 weeks. We measured parameters related to insulin resistance, serum lipid levels, liver fatty acid (FA) content and steatosis score, concomitantly with those associated with mitochondrial energy functions modulated by the transcriptional coactivator PGC-1a.

Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View.

Nonalcoholic fatty liver disease (NAFLD) is present in approximately 25% of the population worldwide. It is characterized by the accumulation of triacylglycerol in the liver, which can progress to steatohepatitis with different degrees of fibrosis, stages that lack approved pharmacological therapies and represent an indication for liver transplantation with consistently increasing frequency. In view that hepatic steatosis is a reversible condition, effective strategies preventing disease progression were addressed using combinations of natural products in the preclinical high-fat diet (HFD) protocol (60% of fat for 12 weeks).

Iron-induced derangement in hepatic Δ-5 and Δ-6 desaturation capacity and fatty acid profile leading to steatosis: Impact on extrahepatic tissues and prevention by antioxidant-rich extra virgin olive oil.

The administration of iron induces liver oxidative stress and depletion of long-chain polyunsaturated fatty acids (LCPUFAs), n-6/n-3 LCPUFA ratio enhancement and fat accumulation, which may be prevented by antioxidant-rich extra virgin olive oil (AR-EVOO) supplementation. Male Wistar rats were subjected to a control diet (50 mg iron/kg diet) or iron-rich diet (IRD; 200 mg/kg diet) with alternate AR-EVOO for 21 days. Liver fatty acid (FA) analysis was performed by gas-liquid chromatography (GLC) after lipid extraction and fractionation, besides Δ-5 desaturase (Δ-5 D) and Δ6-D mRNA expression (qPCR) and activity (GLC) measurements.

High-fat diet induces mouse liver steatosis with a concomitant decline in energy metabolism: attenuation by eicosapentaenoic acid (EPA) or hydroxytyrosol (HT) supplementation and the additive effects upon EPA and HT co-administration.

High-fat-diet (HFD) feeding is associated with liver oxidative stress (OS), n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) depletion, hepatic steatosis and mitochondrial dysfunction. Our hypothesis is that the HFD-induced liver injury can be attenuated by the combined supplementation of n-3 LCPUFA eicosapentaenoic acid (EPA) and the antioxidant hydroxytyrosol (HT). The C57BL/6J mice were administered an HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg kg day), HT (5 mg kg day), or EPA + HT (50 and 5 mg kg day, respectively) for 12 weeks.

Docosahexaenoic acid and hydroxytyrosol co-administration fully prevents liver steatosis and related parameters in mice subjected to high-fat diet: A molecular approach.

Attenuation of high-fat diet (HFD)-induced liver steatosis is accomplished by different nutritional interventions. Considering that the n-3 PUFA docosahexaenoic acid (DHA) modulates lipid metabolism and the antioxidant hydroxytyrosol (HT) diminishes oxidative stress underlying fatty liver, it is hypothesized that HFD-induced steatosis is suppressed by DHA and HT co-administration. Male C57BL/6J mice were fed a control diet (CD; 10% fat, 20% protein, 70% carbohydrates) or a HFD (60% fat, 20% protein, 20% carbohydrates) for 12 weeks, without and with supplementation of DHA (50 mg/kg/day), HT (5 mg/kg/day) or both.

Combined docosahexaenoic acid and thyroid hormone supplementation as a protocol supporting energy supply to precondition and afford protection against metabolic stress situations.

Liver preconditioning (PC) refers to the development of an enhanced tolerance to injuring stimuli. For example, the protection from ischemia-reperfusion (IR) in the liver that is obtained by previous maneuvers triggering beneficial molecular and functional changes. Recently, we have assessed the PC effects of thyroid hormone (T single dose of 0.