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Bad fats oxidized polyunsaturated and transfats

Polyunsaturated Fats, Rancidity, Trans Fats, & Health http://healthfully.org/dja4

Rancidification, the product of which can be described as rancidity, is the process which causes a substance to become rancid, that is, having a rank, unpleasant smell or taste. Specifically, it is the  hydrolysis and/or autoxidation of fats into short-chain aldehydes and ketones which are objectionable in taste and odor.[Hydrolytic   . rancidity refers to the odor that develops when triglycerides are hydrolyzed and free fatty acids are released. This reaction of lipid with water sometimes requires a catalyst, but results in the formation of free fatty acids and salts of free fatty acids. In particular, short-chain fatty acids, such as common butter fats, are odorous….. Oxidative rancidity is associated with the degradation by oxygen in the air. Via a free radical process, the double bonds of an unsaturated fatty acid can undergo cleavage, releasing volatile aldehydes and ketones. Oxidation primarily occurs with unsaturated fats. For example, even though meat is held under refrigeration or in a frozen state, the poly-unsaturated fat will continue to oxidize and slowly become rancid…. Rancidification can produce potentially toxic compounds associated with long-term harmful health effects concerning advanced aging, neurological disorders, heart disease, and cancer. The effectiveness of water-soluble antioxidants is limited in preventing direct oxidation within fats, but is valuable in intercepting free radicals that travel through the aqueous parts of foods. A combination of water-soluble and fat-soluble antioxidants is ideal, usually in the ratio of fat to water.  http://en.wikipedia.org/wiki/Rancidification  

 

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Rancidification, the product of which can be described as rancidity, is the process which causes a substance to become rancid, that is, having a rank, unpleasant smell or taste. Specifically, it is the  hydrolysis and/or autoxidation of fats into short-chain aldehydes and ketones which are objectionable in taste and odor.[Hydrolytic   . rancidity refers to the odor that develops when triglycerides are hydrolyzed and free fatty acids are released. This reaction of lipid with water sometimes requires a catalyst, but results in the formation of free fatty acids and salts of free fatty acids. In particular, short-chain fatty acids, such as common butter fats, are odorous….. Oxidative rancidity is associated with the degradation by oxygen in the air. Via a free radical process, the double bonds of an unsaturated fatty acid can undergo cleavage, releasing volatile aldehydes and ketones. Oxidation primarily occurs with unsaturated fats. For example, even though meat is held under refrigeration or in a frozen state, the poly-unsaturated fat will continue to oxidize and slowly become rancid…. Rancidification can produce potentially toxic compounds associated with long-term harmful health effects concerning advanced aging, neurological disorders, heart disease, and cancer.… The effectiveness of water-soluble antioxidants is limited in preventing direct oxidation within fats, but is valuable in intercepting free radicals that travel through the aqueous parts of foods. A combination of water-soluble and fat-soluble antioxidants is ideal, usually in the ratio of fat to water.  http://en.wikipedia.org/wiki/Rancidification  

 

 

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Malonyldialdehyde (MDA) formation, a measure of polyunsaturated fat autoxidation, was estimated in normal human red cells incubated in vitro. Exposure to oxygen under a variety of conditions did not induce autoxidation. Exposure to hydrogen peroxide was either by the addition of a hydrogen peroxide solution or by incubation in an atmosphere saturated with hydrogen peroxide vapour. A pattern of MDA formation was established with both methods…. A number of recognized antioxidants inhibited peroxide-induced MDA formation. Inhibition was proportional to the logarithm of the antioxidant concentration.

The Autoxidation of Human Red Cell Lipids induced by Hydrogen Peroxide, 1971  http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.1971.tb00790.x/abstract

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Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturatedfatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess especially reactive hydrogens. As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination.  Initiation is the step in which a fatty acid radical is produced. The most notable initiators in living cells are reactive oxygen species (ROS), such as OH and HO2, which combines with a hydrogen atom to make water and a fatty acid radical.  The fatty acid radical is not a very stable molecule, so it reacts readily with molecular oxygen, thereby creating a peroxyl-fatty acid radical. This radical is also an unstable species that reacts with another free fatty acid, producing a different fatty acid radical and a lipid peroxide, or a cyclic peroxide if it had reacted with itself. This cycle continues, as the new fatty acid radical reacts in the same way.[1]  The end products of lipid peroxidation are reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenal(HNE), the second one being known also as "second messenger of free radicals" and major bioactive marker of lipid peroxidation, due to its numerous biological activities resembling activities of reactive oxygen species. http://informahealthcare.com/toc/fra/44/10  In addition, end-products of lipid peroxidation may be mutagenic and carcinogenic.[3] For instance, the end-product malondialdehyde reacts with deoxyadenosine and deoxyguanosine in DNA, forming DNA adducts to them, primarily M1G.[3]  Certain diagnostic tests are available for the quantification of the end-products of lipid peroxidation, to be specific, malondialdehyde (MDA).[3] The most commonly used test is called a TBARS Assay (thiobarbituric acid reactive substances assay). Thiobarbituric acid reacts with malondialdehyde to yield a fluorescent product. However, there are other sources of malondialdehyde, so this test is not completely specific for lipid peroxidation.[5] In recent years development of immunochemical detection of HNE-histidine adducts opened more advanced methodological possibilities for qualitative and quantitative detection of lipid peroxidation in various human and animal tissues (http://informahealthcare.com/toc/fra/44/10) as well as in body fluids, including human serum and plasma samples (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757688/).  Wiki.


The Autoxidation of Human Red Cell Lipids induced by Hydrogen Peroxide, 1971  http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.1971.tb00790.x/abstract

Malonyldialdehyde (MDA) formation, a measure of polyunsaturated fat autoxidation, was estimated in normal human red cells incubated in vitro. Exposure to oxygen under a variety of conditions did not induce autoxidation. Exposure to hydrogen peroxide was either by the addition of a hydrogen peroxide solution or by incubation in an atmosphere saturated with hydrogen peroxide vapour. A pattern of MDA formation was established with both methods…. A number of recognized antioxidants inhibited peroxide-induced MDA formation. Inhibition was proportional to the logarithm of the antioxidant concentration.

 

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BIOLOGICAL RANCIDIFICATION 

Lancet 1969 Volume 294, Issue 7622, 27 September 1969, Pages 684–688.  http://www.sciencedirect.com/science/article/pii/S0140673669903900

Autoxidation, a destructive interaction between unsaturated fats and molecular oxygen, accounts for many industrial and natural-decay processes. The possibility that the body fats might undergo a similar kind of degradation is still largely ignored—perhaps because the irregular irreversible pattern of this type of process seems at odds with the enzyme-controlled reversible pathways of traditional biochemistry. Yet work with mitochondria and other biological preparations has shown that the processes commonly grouped together as " degeneration ", " fatigue ", and " ageing " (none of which have a basis in classical enzymology) develop in close parallel with evidence of rancidification.

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Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturatedfatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess especially reactive hydrogens. As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination.  Initiation is the step in which a fatty acid radical is produced. The most notable initiators in living cells are reactive oxygen species (ROS), such as OH and HO2, which combines with a hydrogen atom to make water and a fatty acid radical.  The fatty acid radical is not a very stable molecule, so it reacts readily with molecular oxygen, thereby creating a peroxyl-fatty acid radical. This radical is also an unstable species that reacts with another free fatty acid, producing a different fatty acid radical and a lipid peroxide, or a cyclic peroxide if it had reacted with itself. This cycle continues, as the new fatty acid radical reacts in the same way.[1]  The end products of lipid peroxidation are reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenal(HNE), the second one being known also as "second messenger of free radicals" and major bioactive marker of lipid peroxidation, due to its numerous biological activities resembling activities of reactive oxygen species. http://informahealthcare.com/toc/fra/44/10  In addition, end-products of lipid peroxidation may be mutagenic and carcinogenic.[3] For instance, the end-product malondialdehyde reacts with deoxyadenosine and deoxyguanosine in DNA, forming DNA adducts to them, primarily M1G.[3]  Certain diagnostic tests are available for the quantification of the end-products of lipid peroxidation, to be specific, malondialdehyde (MDA).[3] The most commonly used test is called a TBARS Assay (thiobarbituric acid reactive substances assay). Thiobarbituric acid reacts with malondialdehyde to yield a fluorescent product. However, there are other sources of malondialdehyde, so this test is not completely specific for lipid peroxidation.[5] In recent years development of immunochemical detection of HNE-histidine adducts opened more advanced methodological possibilities for qualitative and quantitative detection of lipid peroxidation in various human and animal tissues (http://informahealthcare.com/toc/fra/44/10) as well as in body fluids, including human serum and plasma samples (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757688/).  Wiki.

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http://informahealthcare.com/doi/full/10.3109/10715762.2010.498478

Pathological aspects of lipid peroxidation

October 2010, Vol. 44, No. 10 , Pages 1125-1171 (doi:10.3109/10715762.2010.498478)

Read More: http://informahealthcare.com/doi/full/10.3109/10715762.2010.498478  Lipid peroxidation in human diabetes: From the beginning to the end (R Pamplona, J Serrano, J Boada, V Ayala, A Negre-Salvayre, R Salvayre, M Portero-Otin)

Abstract

Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.

 

The prevalence of diabetes mellitus (DM) will reach 300 million in 20 years, in a close relationship with over-weight. This is mainly due to consumption of high-energy diets unbalanced with physical activity. Both chronic hyperglycaemia and hyperglycaemic peaks during post-prandial periods constitute a factor for increased oxidative stress in diabetes. In this short review we will depict the evidences in human studies of the importance of lipid oxidation in the development of diabetes from impaired fasting glucose up to DM chronic complications.

Extracellular evidences of lipid peroxidation in human diabetes. MDA levels are increased in T2DM patients with complications compared with those non-complicated [280], a fact also present in comparison with non-DM individuals [281–284]. Besides, other aldehydes directly related to hyperglycaemia [285] as glyoxal and methylglyoxal, also increase in T1DM patients as a very early event after hyperglycaemia [286,287]. Interaction between hyperglycaemia and lipid peroxidation also includes the fact that MDA increases in vivo modification by glycation, as recently shown in chronic renal failure patients [288]. Other lipoxidation markers, as the isoketal F2-isoprostanes [289], oxidized cholesterol [290] and increased conjugated linolenic acid [291] also increase in DM patients. It has also been shown that TBARS increase with the degree of metabolic impairment, from healthy patients to T2DM in serum [292]. However, this later marker has been criticized in the context of human diabetes, due to lack of specificity [287]. Furthermore, hyperglycaemia, before insulinization, leads to increased lipid peroxidation in humans [293–295]. Recent data show that HDL from T2DM patients is modified by lipid oxidation, in a niacine-preventable fashion [296]. Similarly, T1DM patients exhibit elevated concentration of spin-trapped alpha-phenyl-tert-butylnitrone adducts, measured by electron paramagnetic resonance spectroscopic detection, as well as lipid-derived oxygen-centred alkoxyl. This was accompanied by increased levels of lipid hydroperoxides, with diminished levels of lycopene and retinol [297]. These findings are in accordance with those present in T2DM, where the same adducts were increased, in the form of alkoxyl free radicals derived from the peroxidation of lipid membranes [298]. Since direct spectroscopic evidences of lipid peroxidation are correlated with lipid hydroperoxides, it is suggested that metal-induced decomposition of those species are the precursors of alkoxyl radicals that are thermodynamically able to further propagate oxidative damage to proteins.

In plasma, those lipids may arise from phospholipid moieties belonging to either endothelial cells or erythrocytes, even from circulating lipids. The implication of erythrocytes is sustained by increased MDA levels in erythrocyte ghost membranes of T1DM, when compared with euglycemic individuals [283]. In line with this, pioneering work of Jain and colleagues [299,300] led to the identification of lipid peroxidation as an important factor increasing erythrocyte fragility in human diabetes with a good correlation with glycaemic control.

The initiation agent in the absence of mitochondrial activities (i.e. in plasma) should be the superoxide resulting from glucose and glycation products decomposition [301], in accordance to pioneering work by Hunt et al. [302]. This work evidenced an increase in hydroxyl radicals in the presence of glucose (at concentrations present in human diabetes), in a process termed glucose auto-oxidation. This process, even in non-diabetic states, may contribute to the increased lipoxidative stress evidenced during oral glucose tolerance tests [303]. In accordance with this, T1DM patients show increases in plasma MDA levels after standardized meals [304]. Not only do diabetes patients show increased lipoxidation: it has been demonstrated that MDA and F2-isoprostanes in plasma correlate with glycaemic indexes of meals, suggesting that even in euglycaemia post-pandrial increases in oxidative stress lead to increased lipid peroxidation [298,305].

Besides nutritional supplementation, also correcting in some instances lipid peroxidation, treatment aimed at tackling basic mechanisms of chronic diabetes complications, such as aldose reductase pathway, also show some effect in lipid peroxidation. Thus, the use of an inhibitor of aldose reductase could specifically reduce lipid hydroperoxides in erythrocytes in T2DM patients after 3 months of treatment. This reinforces the concept of an adequate choice for an indicator of lipid peroxidation damage, as other markers, such as plasma TBARS, MDA-modified LDL or even vitamin E were not affected by this treatments [306].

In all these evidences reported for human subjects, it is demonstrated that in a close relationship with glycaemic control, both T1DM and T2DM leads to increased extracellular lipid peroxidation, potentially contributing to their development and complications. Besides obvious solutions, as insulinization, nutritional and advanced pharmacological therapies could also improve lipoxidative status, aimed at preventing long-term complications of DM.

Intracellular evidences of lipid peroxidation in diabetes: The skeletal muscle case and involvement in insulin resistance. Since the key works led by Brownlee and colleagues [307–309] in which oxidative stress was identified as an unifying mechanism behind other recognized pathways between hyperglycaemia and chronic complications in endothelial cells, several other works have extended this concept to other cells and tissues. High glucose levels, in T2DM high fatty acid content in muscle cells, are associated both as a cause and/or a consequence of mitochondrial function [310]. As a cause, in humans, even a short consumption of high-fat diets led to increases in intracellular lipids in skeletal muscles in healthy individuals [311]. Also, in individuals with relatives suffering of T2DM, a small reduction in mitochondrial function is accompanied by an unexpectedly high accumulation in intracellular lipid contents [312,313]. As a consequence, lipids would induce impairment of mitochondrial function. In T2DM patients, plasma FFA levels are significantly and negatively correlated with mitochondrial function, leading to impaired ATP production [314]. Thus, diminished PGC1a levels—a key regulator of energy metabolism—in insulin resistant individuals could be induced by accumulation of intramuscular lipids [315,316].

Mitochondrial ROS (mitROS) can rapidly react with mitochondrial DNA, protein and lipids, thereby leading to oxidative damage. As an example, in skeletal muscle, the fatty acids present in excessive amounts in T2DM patients can be very prone to ROS-induced oxidative damage, resulting in the formation of lipid peroxides. Especially accumulation of fatty acids in the inner mitochondrial membrane of mitochondria, at the site where ROS are formed, would be susceptible to peroxidation, subsequently inducing oxidative damage to the mitochondrial machinery. In this line, it should be remarked that the percentage of total electron flow directed to free radical generation in mitochondria is not constant in different tissues and different conditions inside a given tissue, which suggests that mitROS generation is more than a simple byproduct of mitochondrial respiration, as frequently assumed, and should be better viewed as a homeostatically controlled variable. Oxygen radical generation at the respiratory chain has been classically attributed to complex III semiquinone [317] and complex I flavin mononucleotide [318,319] or complex I FeS clusters near the rotenone-binding site [320]. Besides those structural characteristics, adaptable variables such as entry of substrates could also play a key role in determining mitROS production. Thus, β-oxidation controls entry of fatty acids into mitochondria, although this system does not prevent completely the interaction of fats with mitochondria and hence its contact with mitROS sources. This is due to the fact that physical interaction, via ‘flip-flop’ mechanism, could allow matrix membrane entry of excess of fatty acids [321]. Since in this location they cannot enter energy production due to the absence of acyl-CoA synthetase, they remain into the inner mitochondrial membrane, exposed to mitROS. Alternatively, and analogously with the mitochondrial changes induced by high glucose concentrations, increased fatty acid efflux to mitochondria could directly increase mitROS production, more glucose being oxidized in the TCA cycle. This situation drives one to push more electron donors (NADH and FADH2) into the electron transport chain, thus leading to an increase in ROS generation [307]. In this situation, there is a higher degree of reduction of complexes I and III, increasing their rate of ROS production. Likewise, in the insulin resistance syndrome, there is an increased free fatty acids flux from adipocytes into arterial endothelial cells that would result in increased fatty acid oxidation by mitochondria [322,323]. Since both β-oxidation of fatty acids and oxidation of fatty acid-derived acetyl CoA by the TCA cycle generate the same electron donors (NADH and FADH2) generated by glucose oxidation, increased FFA oxidation may cause mitochondrial over-production of ROS by the mechanism above described for hyperglycaemia.

The mechanism notwithstanding, muscle cells from obese pre-diabetic patients show increased intramyocellular lipid peroxidation [324]. As in ageing, where high lipid peroxidation is associated to lower lifespan by increased oxidation-derived damage to proteins and nucleic acids [325], it is suggested that lipid peroxidation in mitochondria from insulin resistant individuals could lead to mitochondrial function impairment [310], thereby generating a vicious circle. In accordance with this, high fat diets induced increased mitROS production [326].

Losing to win: Uncoupling mechanisms for mitROS control in DM. Mitochondrial uncoupling through proton leakage has been proposed as a mechanism to lower mitROS. This is especially interesting as the relationship between proton gradient and mitROS is exponential, so a small loss in ATP production could have a high trade-off value [327]. In human ageing, this mild mitochondrial uncoupling could explain why some muscles show more age-related losses than others [328].

As known since the early 1960s, fatty acids are capable to induce mitochondrial uncoupling [329]. Our previous data show that a homeostatic mechanism depending on lipid peroxidation controls mitROS production through mild uncoupling. Thus, increased mitROS production generates 4-HNE, which, besides a signalling role, shows also both a propagation role and also an uncoupling role, leading to diminished mitROS production [330]. In T2DM, though speculatively, this mechanism would be overwhelmed, as increased lipid peroxidation derived protein damage has been evidenced in samples from animal models of this disease [331]. Furthermore, expression of uncoupling proteins leads to both diminished lipid peroxidation [332] and lipid peroxidation-derived damage: in mitochondria from UCP3-under-expressing models significantly higher levels of lipoxidative damage than wild-type controls were found, suggesting that UCP3 functions in vivo as part of the antioxidant defences of the cell [333], a finding also observed by other authors [334]. Noteworthy, T2DM patients and insulin-resistant individuals show a diminished value of UCP3 protein levels in muscle, suggesting that an impairment in the expression of this protein and, possibly, other mitochondrial mechanisms for mitROS normalization could underlie mitochondrial dysfunction in insulin-resistant and diabetic states [316,335].

In conclusion, these data reveal that not only extracellular lipid peroxidation is important for chronic complications, but also intracellular lipid peroxidation could be a key factor in the relationship between unbalanced energy homeostasis and T2 DM rising incidence.

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http://ajpendo.physiology.org/content/299/6/E879.short

Protective and detrimental effects of 4-hydroxyalkenals in diabetes

Y. Riahi, G Cohen, O Shamni, S Sasson

The peroxidation of polyunsaturated fatty acids is intensified in diabetes. The peroxidation of n-3 and n-6 polyunsaturated fatty acids and the production of 4-hydroxyalkenals are intensified in diabetes due to the pro-oxidative environment induced by prolonged hyperglycaemia [336]. Of particular interest are the peroxidation products of n-6 poly-unsaturated fatty acids, namely 4-HNE and 4-HDDE [67,70,337]. The former is the peroxidation product of 15-hydroperoxyeicosatetraenoic acid (15-HpETE) and 13-hydroperoxyoctadecadienoic acid (13-HpODE), which are 15-lipoxygenase (15-LO) metabolites of arachidonic- and linoleic acid, respectively. 4-HDDE is the peroxidation product of 12-hydroperoxyeicosatetraenoic (12-HpETE), the 12-LO metabolite of arachidonic acid [337,338].

The physiological, pathophysiological or cytotoxic effects of 4-hydroxyalkenals depend on their absolute concentrations. The best example is 4-HNE: Esterbauer et al. [67] showed that at concentrations higher than 20 μmol/L it exhibited cytotoxic effects that result from its chemical reactivity and the formation of stable adducts with proteins and nucleic acids, which alter their functions [70]. Bacot et al. [337,339] demonstrated that 4-hydroxyalkenal-induced membrane disorders resulted from the formation of adducts with ethanolamine phospholipids. They also reported that the potency of 4-HDDE in forming such ethanolamine phospholipids-adducts was 3-fold higher than that of 4-HNE [337,338]. Likewise, we found that 4-HDDE induced vascular endothelial cell (VEC) death at significantly lower concentrations than 4-HNE (1 vs 25 mol/L, respectively) [340]. The higher chemical reactivity of 4-HDDE is attributed to the presence of two double bonds and its higher hydrophobicity in comparison with 4-HNE (Log p-values 3.48 and 2.45, respectively) [339].

Normally, the cellular levels of 4-hydroxyalkenals are well-controlled because their precursors, 12- and 15-HpETEs, are effectively reduced by GPx to the corresponding hydroxyl-derivatives 12- or 15-hydroxyeicosatetraenoic acid (12-HETE and 15-HETE) [336]. However, free radicals can slow and even block this pathway by inactivating GPx [337]. This leads to the accumulation of HpETEs, which are then subjected to the free radical-initiated peroxidation process that ends in the generation of 4-HDDE and 4-HNE. Similarly, 13-HpODE is peroxidized to generate 4-HNE. SEVERAL alternative mechanisms for the peroxidation process and the generation of these reactive aldehydes have been proposed [4,341–346]. Common to these models is the primary hydroxyl radical-induced abstraction of hydrogen atom from 12- and 15-HpETE. The resulting radicals interact with free oxygen and further undergo a chain-breaking reaction to generate the corresponding 4-hydroxyalkenals.

Figure 2 depicts the two main routes of arachidonic acid transformation: the common pathway that occurs in metabolically undisturbed cells and the aberrant peroxidation pathway that is induced by an excessive oxidative stress. This model suggests that tissue-specific production of 4-hydroxyalkenals correlates with the specific pattern of expression of lipoxygenases and the biosynthesis of the corresponding HpETEs. This has been demonstrated by Guichardant’s group [337,347] in diabetic rat's retina that expresses 15-LO and generate 4-HNE, but not 4-HDDE. Similarly, Coleman et al. [348] have found that 4-HNE, generated from 15-HpETE, is the major peroxidation product in 3T3-L1 pre-adipocytes. We have found that bovine aortic endothelial cells that express 12-LO generate under hyperglycaemic conditions excessive levels of 4-HDDE, but not 4-HNE [340,349,350]. It is reasonable to suggest that human VEC that also predominantly over-express 12-LO under high glucose conditions preferentially generate 4-HDDE under such conditions [351]. A similar relationship between 12-HpETE and 15-HpETE and the generation of the corresponding 4-HDDE and 4-HNE has been reported by Bacot et al. [337]. We speculate that 4-HDDE is the putative lipid peroxidation product that Bleich et al. [352] have implicated in β-cell dysfunction following cytokine-mediated increased expression of 12-LO. This model also shows that oxidative stress induced by hyperglycaemia diverts the flux of HpETEs from the enzymatic pathway towards the peroxidative arm. This role of free radicals in lipid peroxidation has been demonstrated in several systems [347,353–355].




In addition, hyperglycaemia increases the expression and cellular level of 12- and 15-LO in cells and subsequently the availability of HpETEs to peroxidation. Such induction of 12-LO was discovered in islets of Langerhans from Zucker diabetic fatty rats (a rodent model of T2DM) in comparison with the non-diabetic controls [356] and in islets isolated from others types of diabetic rats [357]. We investigated the pattern of expression of 12-LO in primary cultures of aortic endothelial and smooth muscle cells and discovered that high glucose levels increased the cell content of 12-LO (but not 15-LO) [340,349,350]. Similarly, Natarajan et al. [358] reported that elevated glucose levels increased the expression of 12-LO in porcine aortic SMC.


These findings suggest that the impact of hyperglycaemia on lipid peroxidation is synergetic: the expression of lipoxygenases is elevated in cells and the products of these enzymes are channelled to peroxidation and an augmented formation of 4-hydroxyalkenals. This model predicts an increased abundance of 4-hydroxyalkenals in diabetic individuals. Indeed, Toyokuni et al. [359] found a marked increase in the level of 4-HNE-modified albumin in sera of T2DM patients in comparison with normoglycaemic subjects. These elevated levels were attributed to an increased generation of 4-HNE in peripheral tissues. Similar observations were made in Zucker obese rats [360]. Hitherto, no such determinations of 4-HDDE and 4-HDDE-protein adducts in diabetic patients have been reported. Nevertheless, Guichardant et al. [347] measured significant amounts of 4-HDDE metabolites along with 4-HNE and 4-HHE metabolites in urine samples of healthy individuals.


Roles of 4-hydroxyalkenals in diabetes. Products of lipid peroxidation can affect cells in diabetic subjects in two major ways, depending on their concentrations in cells and organs. First, high levels of 4-hydroxyalkenals induce detrimental effects and substantial cell damage that lead to severe complications of diabetes. Second, intermediate non-toxic concentrations of these compounds may attenuate cellular signalling and metabolic pathways, which may be either unfavourable or protective.


Role of 4-hydroxyalkenals in β-cell dysfunction. The tendency of 4-hydroxyalkenals to bind covalently to amino acid moieties (i.e. histidine, lysine, cysteine) in proteins, guanine nucleotides in DNA and phospholipids underlies their significant contribution to the development of complications of diabetes. Foremost, the failure of pancreatic β-cells to adequately increase insulin secretion in response to hyperglycaemia is considered, together with peripheral insulin resistance, a critical factor in the development of T2DM. Hyperglycaemia-induced free radical formation is a major contributing factor to the deterioration of β-cell in T2DM. Various studies have alluded to a detrimental role of 4-hydroxyalkenals in this process: Bleich et al. [361] linked the increased expression of 12-LO in islets of diabetic rats to impaired insulin secretory function. Prasad et al. [362] found that over-expression of 12-LO in cultured INS-1E β-cells halved their glucose-induced insulin secretory capacity. Similarly, the incubation of isolated rat islets with a high level of 4-HNE (100 M) significantly lowered their insulin secretory capacity [363]. Conversely, 12-LO knockout mice did not develop glucose intolerance and β-cell dysfunction when fed a diabetogenic high fat diet [364]. In addition, such 12-LO knockout mice were highly resistant to streptozotocin-induced diabetes and their isolated islets maintained good insulin secretory capacity following treatment with inflammatory cytokines. Collectively, these finding suggest that 12-HpETE, the immediate product of 12-LO, and its peroxidation products adversely affect β-cell function [352]. This idea was confirmed when over-expression of 12-LO in cultured INS-1E β-cells abrogated glucose-induced insulin secretion [362]. Further support comes from the finding that β-cell death in rodent and human islets exposed in vitro to inflammatory cytokines (i.e. IL-1β, INFγ, TNFα) was prevented in the presence of baicalein, a specific inhibitor of 12-LO, whereas incubation of the cells with 12-LO metabolites reduced basal insulin secretion and increased cell death [365]. It has been suggested that 4-HNE at non-toxic concentrations inhibits cell growth and induces accumulation of cells in the G0/G1 phase of the cell cycle [366]. Plausibly, a similar inhibitory effect of 4-HNE on β-cells replications may reduce their mass in islets, a phenomenon characteristic to diabetic islets.


The autoimmune and cytokine-mediated destruction of β-cells in Type-1 diabetes has also been associated with over-production of reactive aldehydes, such as 4-HNE. The non-obese diabetic (NOD) mice usually develop severe autoimmune insulitis and diabetes. However, the expression of an inactive 12/15-LO in these mice rendered them resistant to the development of diabetes [367]. Similarly, Bleich et al. [352] found that islets isolated from 12-LO knockout mice were resistant to cytokine-induced damage. Suarez-Pinzon et al. [368] also identified a key role for 4-HNE and other cytotoxic aldehydes in the destruction of rat pancreatic islet β-cells by cytokines. Other β-cell lines (RINm5F and HIT-T15) were particularly susceptible to 4-HNE, which caused 75–100% cell death at 50 M [369]. It was suggested that 4-HNE and other lipid peroxidation products induce apoptosis in RINm5F cells [370]. Noteworthy, not all cells are equally susceptible to 4-hydroxyalkenal-induced damage due to a variable expression of the major detoxifying enzymes glutathione S-transferase (GST, i.e. Gst-3 and Gst-ω1) and fatty aldehyde dehydrogenase (FALDH, i.e. Aldh3a1) [348]. GSTs detoxify 4-hydroxyalkenals through conjugative reactions, while FALDH transforms the aldehyde group into a carboxylic moiety to produce 4-hydroxy-2E,6Z-dodecadienoic acid (4-HDDA) from 4-HDDE and 4-hydroxy-2E-nonenoic acid (4-HNA) from 4-HNE. Both 4-HNA and 4-HDDA were identified in human urine [347] and in various cells and tissues [67,371]. Only few studies addressed the possibility that these metabolites are biologically active. Murphy et al. [372] reported that 4-HNA bound to the γ-butyrate receptor in the CNS, while Echtay et al. [330] suggested that it uncoupled proton conductance in mitochondria. The susceptibility of β-cells to oxidative stress- and ROS-induced damages has been attributed to their inherent poor intrinsic antioxidant defence [373–376]. This, coupled to a progressive 4-hydroxyalkenal-induced inactivation of FALDH and GST, may exaggerate β-cell dysfunction. Of interest is also the report on an impaired hepatic disposal of 4-HNE in diabetic rats [377]. Consequently, the slow clearance may extend the exposure of β-cells to 4-hydroxyalkenals and further intensify β-cell dysfunction.


Role of 4-hydroxyalkenals in macrovascular diseases. Hyperglycaemia is an established major and independent risk factor in the development of cardiovascular disease in diabetes [378–381]. Endothelial cell dysfunction is the earliest event in the development of atherosclerotic lesions in blood vessels. This condition may result from a direct oxidative damage and over-production of 4-hydroxyalkenals that compromise the integrity and functions of the endothelial cell monolayer. For instance, Minekura et al. [382] found that 4-HNE significantly reduced the expression of adhesion molecules (i.e. ICAM-1, VCAM-1) induced by TNF-α and NF-κB activation in primary cultures of human aortic endothelial cells. Tetrahydrobiopterin (THB), the cofactor of endothelial nitric oxide synthase (eNOS), is particularly susceptible to inactivating interactions with 4-HNE. The inactivation and lack of THB induce uncoupling of the enzymatic reaction of eNOS, which leads to the generation of superoxide radicals that further exacerbate the oxidative damage [383]. Interestingly, 4-HNE has been implicated in macrophage activation and their transformation to foam cells in diabetic blood vessels [5]. This is partly due to the 4-HNE capacity to increase the expression of class A scavenger receptors, which enhances macrophage foam cell formation [384]. Moreover, oxLDL has a considerable capacity to covalently bind 4-HNE [385].



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Figure 2. Mechanism of 4-hydroxyalkenal generation. The enzymes 12- and 15-lipoxygenase (12- and 15-LO) metabolize arachidonic acid to the corresponding hydroperoxyeicosatetraenoic acids (12- and 15-HpETE), which are further converted by glutathione peroxidase (GPx) to 12- or 15-hyroxyeicostetraenoic acid (12- and 15-HETE). Radical induced inactivation of GPx diverts 12- and 15-HpETE to the peroxidation pathway to ultimately generate the respective 4-hydoxdodecadienal (4-HDDE) and 4-hdroxynonenal (4-HNE).




The smooth muscle cell layer in blood vessels is also a target for 4-HNE, which induces a marked mitogenic response, characteristic to the early event in atherosclerosis [386–388]. High levels of 4-HNE were associated with other effects in smooth muscle cells, such as apoptosis [389], autophagy [390], cytotoxicity [391], production of TGF-β [392], impaired PDGF receptor activity [393] and enhanced matrix metalloproteinase-2 production [394,395].


The physiological relevance of these in vitro studies has been corroborated by Yamanouchi et al. [396], who studied streptozotocin-diabetic APA Syrian hamsters that developed atheromatous lesions. Immunohistochemical analysis of foam cells in the fatty streaks in blood vessels showed a significant increased abundance of 4-HNE-protein adducts. Similarly, Meng et al. [397] found a high content of 4-HNE-protein adducts in aortae of streptozotocin (STZ)-diabetic rats. Recently, Mattson [53] suggested in a comprehensive review a central role of 4-HNE in obesity, in the metabolic syndrome and in vascular and neurodegenerative disorders. Of particular interest in this review is the suggestion to use 4-HNE as a target to prevent and treat the metabolic syndrome and associated diseases. Two main st rategies were put forward: to reduce 4-HNE production by suppressing lipid peroxidation or by its detoxification.


Other complications


The aetiology of other peripheral complications in diabetes has also been linked to aberrant interactions of 4-HNE. For example, Polak and Zagorski [398] found significantly higher levels of 4-HNE and MDA in diabetic patients with retinopathy in comparison with patients that did not develop this complication. The presence of AGEs and 4-HNE-protein adducts was evidenced immunohistochemically in the glomerulus in diabetic nephropathy in humans [399,400]. Others found that 4-HNE mimicked features of diabetic neuropathy by inducing mitochondrial dysfunction and aberrant axonal outgrowth in adult sensory neurons isolated form rats [401,402]. It has been shown that effective quenching of 4-HNE can greatly improve the wound healing process, which is a serious complication in diabetes [403].


Non-toxic interactions of 4-hydroxyalkenals in diabetes. Unfavourable interactions: By their tendency to form covalent bonds with various amino acid moieties, 4-hydroxyalkenals can modify structures of proteins even at non-toxic levels and alter their function. Several reports have addressed such interactions of 4-HNE that affect signalling pathways in cells [404–406]. Some interactions have been associated with cell differentiation, transcription factors regulation, activation of stress kinases, mitogenic response, stimulation of heat shock proteins or modulation of transduction mechanisms. Demozay et al. [407] have demonstrated the role of 4-HNE in attenuating the insulin transduction mechanism and inducing insulin resistance in 3T3-LI adipocytes. Incubation of these cells with non-toxic concentrations of HNE significantly decreased the level of the insulin receptor substrate (IRS)-1/2 proteins. This led to a down-regulated response of downstream targets of the insulin transduction pathway, leading to insulin resistance. The underlying mechanism was the formation of 4-HNE-IRS protein adducts and their rapid degradation. Grimsrud et al. [408] performed a thorough LC-ESI MS/MS analysis of proteins from epididymal adipose tissue of diabetic mice and identified a number of regulatory proteins that bound 4-HNE that were linked to oxidative stress responses and the development of insulin resistance.


Glucose transporters are also targets for 4-HNE. Reagan et al. [409] found an increased level of 4-HNE conjugation with glucose transporter-3 (GLUT-3) in the hippocampus of diabetic rats and linked it to decreased hippocampal neural glucose utilization. It is not clear whether 4-HNE similarly interacts with the ubiquitous GLUT-1, the hepatic and β-cell specific GLUT-2 or the insulin-sensitive GLUT-4.


Protective interactions: We have discovered that VEC exposed to high glucose levels can reduce the rate of glucose uptake and prevent adverse effects associated with an increased influx of glucose. Specifically, these cells reduced the cellular level of their principal glucose transporter GLUT-1 mRNA and protein, as well as its plasma membrane content [349,350,410]. High glucose also increased the expression of 12-LO and the production of 12-HpETE and 12-HETE. Pharmacological inhibition of 12-LO completely blocked these high glucose-induced down-regulatory effects [349–351]. The reduced expression of GLUT-1 in VEC exposed to high glucose resulted from post-transcriptional destabilization and degradation of GLUT-1 mRNA. The protein calreticulin, which was also over-expressed under high glucose conditions, bound to a specific 10-nucleotide sequence in the 3′-UTR of GLUT-1 mRNA, destabilized the molecule and rendered it susceptible to nuclease digestion [411]. We also discovered that the expression of calreticulin was augmented in blood vessels of diabetic animals [411]. Collectively, our studies suggest a functional link between 12-LO and its metabolites to GLUT-1 mRNA destabilization by calreticulin.


We have recently found [340] that the augmented expression of 12-LO in VEC under high glucose conditions was accompanied with a marked increase in the generation and secretion of 4-HDDE, but not 4-HNE. Moreover, using pharmacological and molecular approaches we proved that 4-HDDE was an endogenous ligand of the Peroxisome Proliferator-Activated Receptor (PPAR)-δ in these cells. When added to cells at non-toxic concentrations (50 nM) 4-HDDE activated PPARδ, which specifically interacted with a PPAR-response element in the calreticulin gene and augmented its expression. Previous studies have shown that PPARδ preferentially interacts with unsaturated fatty acids and eicosanoids [406,412]. X-ray analyses of crystal structures of the PPARδ ligand binding domain (LBD) identified a network of hydrogen bonds with His413, Tyr427, His287 and Thr253 involved in the interaction with eicosapentanoic acid [413]. Interestingly, His413 has also been implicated in a hydrogen-bonding interaction with the 4-hydroxy group of 4-HNE [348]. The sites involved in 4-HDDE interaction with the LBD of PPARδ have not been identified yet. This natural protective mechanism against the deleterious effects of hyperglycaemia in vascular cells may explain why some diabetic patients never develop cardiovascular complications, as was found in the Adult Treatment Panel III trial [414]. Figure 3 depicts our working hypothesis: patients who moderately increase the generation of 4-HDDE in VEC under hyperglycaemic conditions benefit from its protective interaction with PPARδ and the subsequent reduction in GLUT-1 levels. When 4-HDDE production is not controlled, it adversely interacts with proteins, DNA and phospholipid and causes substantial damage to the cells. Theoretically, low levels of 4-hydroxyalkenals in VEC may result from a moderate increase in 12/15- LO expression and/or an efficient neutralization of 4-hydroxyalkenals.




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The role of oxidative stress is very important in different liver diseases, mainly in alcoholic and non-alcoholic steatohepatitis and liver cirrhosis, furthermore in chronic viral hepatitis, especially in chronic hepatitis C as well as in primary hepatocellular cancer (HCC). The main processes producing free radicals in mammals are the following: mitochondrial oxidative metabolism providing energy supply, microsomal drug-metabolizing enzyme system, biosynthesis of prostaglandins, constitutive and inducible NO-synthase activity, free radical-producing reactions of phagocytes, monocytes, macrophages and Kupffer's cells and auto-oxidation of H2O2 produced in peroxisomes. Another consequence of free radical activity is lipid peroxidation [445]. In the mechanism of oxidative stress and also in its biological consequences, free radicals can attack small molecules containing thiol and amine groups as well as macromolecules building up the cells. Due to peroxidative damage of the lipids in the cell membrane, permeability changes may occur. Nucleic acid injury can lead to mutations and neoplastic processes of the cells.


The healthy organism is able to prevent the over-production of free radicals. Low oxygen tension of the tissues is a basic condition. Its value is 26 mmHg or less. The primary line of antioxidants consists of representatives of the enzymatic defence. It is supplemented by antioxidant vitamins with scavenger property (vitamins C, A, E, K), the cofactors, compounds containing thiol, phosphor, amine, polyamine, phenols, quinolines, ubiquinone (coenzyme Q), flavonoids, polyenes, glucose, urate, bilirubin, etc.


Non-alcoholic steatohepatitis and liver cirrhosis


Non-alcoholic fatty liver (NAFLD) is a multi-factorial liver disease. It includes a wide spectrum of liver damage characterized by histological changes of alcoholic origin (ranging from uncomplicated fatty liver to steatohepatitis, fibrosis and cirrhosis) in non-alcoholics (< 20 g/day ethanol consumption). The non-alcoholic steatohepatitis (NASH) is part of this disease spectrum, which can progress to hepatic cirrhosis and liver failure. Its primary forms have been proposed to be a manifestation or consequence of the metabolic syndrome, closely related to insulin resistance. It can be caused by several other metabolic factors and viral infections, like hepatitis C. The history of non-alcoholic fatty liver disease is not always benign, sometimes it can be accompanied by hepatocellular carcinoma [446].


Researches have identified the factors that can play a causative role: oxidative stress, lipid peroxidation, abnormal cytokine production, fatty acid metabolic disturbance and insulin resistance. The pathophysiology of non-alcoholic fatty liver involves insulin resistance and production of reactive oxygen species, which stimulate the synthesis of several cytokines (Figure 11) through the up-regulation of their transcription by nuclear factor-κB (NF-κB). The combination of these events causes hepatocyte injury via direct oxidative injury, TNF-α induced apoptosis or inflammation [447].


Role of free fatty acids and insulin resistance. Free fatty acids (FFA) have a decisive role in the development of insulin resistance by being transformed into acyl-CoA intracellularly. In addition to free fatty acids, TNFα and hyperinsulinaemia also play a role in the activation of one of the mechanisms responsible for the negative control of signal transduction of insulin—namely the Ser/Thr-phosphorylation of insulin receptor and insulin-receptor-substrate (IRS) protein—that blocks the signal transduction processes of insulin. In this way muscle cells, hepatocytes and adipocytes all become resistant to insulin. The activity of mitochondrial respiratory chain complexes is reduced in patients with NASH, showing a positive correlation with TNFα levels, insulin resistance (IR) and body mass index (BMI) values.


Inherited defects in the mitochondrial oxidative phosphorylation are supposed to exist in the offspring (diagnosed with IR) of patients with T2DM, leading to disorders in the intramyocellular fatty acid metabolism. The genes dependent on nuclear respiratory factor-1 (NRF-1) that code enzymes, that play crucial roles in the oxidative metabolism and mitochondrial function, are expressed to a lesser extent in diabetes mellitus and IR, possibly due to the reduction of PGC1-expression (PPAR-γ co-activator 1-β and 1-α). In the metabolic syndrome, FFA are released from the abnormal mesenteric tissue to a certain extent depending on the ratio of the β-3- and α-2 receptors in the given fat tissue, as β-3-adrenoreceptors and α-2-receptors are responsible for the induction and the inhibition of the lipolytic process, respectively. Polymorphism of the β-3-receptor has been connected with IR and visceral obesity for a long time, most recently with NAFLD. IR is of decisive importance in how NASH is expressed in a patient, especially in the presence of a reduced mitochondrial oxidation. According to recent research, this involves increased lipolysis in the peripheral tissues, an increase in fatty acid uptake by the hepatocytes, the β-oxidation of the fatty acids taken up by the hepatocytes increases, and the uptake of lipoprotein by the tissues is reduced, due to insufficient lipoprotein lipase. IR is much more severe in patients with NASH than in those diagnosed with ‘simple’ fatty liver.


Mitochondrial dysfunction in NAFLD. Mitochondrial abnormalities are closely related to the pathogenesis of NAFLD, which raised the possibility that NAFLD is a mitochondrial disease [448]. Many genes encoding mitochondrial proteins in skeletal muscle and fat are negatively correlated with body mass, mtDNA depletion in hepatocytes impairs mitochondrial function and causes hepatic steatosis and other liver injuries. Multiple enzymes are involved in mitochondrial β-oxidation and their deficiency may lead to the development of hepatic steatosis.


A number of mechanisms can be considered to explain the mitochondrial dysfunction found in NAFLD patients and animal models. Possible mechanisms include (a) excessive ROS production, (b) increased TNFα expression and (c) altered PGC-1 expression. MRC dysfunction can directly lead to the production of ROS. If electron flow is interrupted at any point in the respiratory chain, the preceding respiratory intermediates can transfer electrons to molecular oxygen to produce superoxide anion and H2O2. MDA and 4-HNE can inhibit mitochondrial cytochrome c oxidase by forming adducts with this enzyme. ROS-induced depletion in mtDNA can severely lower mitochondrial number and function, leading to steatosis and liver lesions. Mitochondrial dysfunction may not only cause fat accumulation, but also may generate ROS and cytokines, contributing to the progression of NAFLD by inducing hepatic inflammation and fibrosis [448].


Non-organ-specific autoantibodies (NOSA); positive fatty liver. Non-organ specific autoantibodies (NOSA) include anti-nuclear antibodies (ANA), smooth muscle antibodies (SMA) and anti-mitochondrial antibodies (AMA). They occur in a variety of non-autoimmune chronic liver disease. Their production could be secondary to or triggered by hepatocellular inflammation and necrosis. NOSA positivity in NAFLD has been found to be more prevalent compared to the general population. We have studied the prevalence of non-organ-specific autoantibodies and their correlates with cytokine release and free radical-antioxidant balance in non-alcoholic fatty liver disease [449]. Prevalence of NOSA positivity was found to be 55% in our NAFLD patients. Autoantibody positive patients showed lower antioxidant capacity: lower SH-group concentration, decreased total antioxidant status and elevated chemiluminescence intensity. We suppose that, similar to alcoholic liver disease, the aldehyde products of lipid peroxidation, such as MDA, can react with proteins and form stable protein adducts, which are very immunogenic and capable of inducing immune response, resulting in generation of antibodies. NAFLD with autoantibody positivity may have a worse prognosis because of the impaired antioxidant status. It can be supposed that the appearance of autoantibodies in NAFLD is triggered by free radical reaction, but further investigations are needed to understand the significance, role and the exact mechanisms of NOSA production in NAFLD [449].


Fatty liver in childhood


According to studies, the idiopathic steatohepatitis is characteristic mostly of obese children of peripubertal age. The development of fatty liver can be attributed to several factors. Pathogenetic causes of lipid accumulation in the hepatocytes—likely in adults—may include (1) reduced oxidation and expenditure of fatty acids; (2) increased synthesis of fatty acids; (3) reduced release of triglycerides from the liver; and (4) increased release of fatty acids from the peripheral fat depots [6]. The pathomechanism has a characteristic two-step form: at first fat is accumulated in the liver cells and then this induces a fibrous reaction. Accumulation of ROS has an important role in both steps. Probably the FFA reaching mitochondria cause saturation of mitochondrial beta-oxidation, creating ROS and lipid peroxides, as well as they activate the CYP2E1 isoform of cytochrome P450 enzyme in hepatocytes and Kupffer cells. Children with NAFLD or NASH have an increased disposition to cardiovascular complications, hyperlipidemia and insulin resistance—or, in the case of alcohol consumption, to alcoholic liver disease—in adulthood. The principal treatment in obese children consists of a diet which is low in fat and poor in refined carbohydrates, as well as physical exercise of medium intensity. Blood glucose and lipid levels should be monitored during the treatment [450].


Fatty liver and hepatitis C viral infection


The significance of fatty liver alteration in the hepatitis C virus (HCV) infection [451] is important because of the decreased viral response to the antiviral drug therapy in these cases. Among patients with HCV genotype 1 infection, the grade of steatosis was correlated with host-related factors, mainly with the presence of the metabolic syndrome. In genotype 3, steatosis degree correlates with liver HCV quantification and serum viral load. In genotype 1, steatosis depends on leptin levels and insulin resistance.


Insulin resistance and hyperinsulinaemia have been found in association with liver fibrosis in hepatitis C [451]. The mechanisms through which insulin resistance promotes fibrosis progression include: oxidative stress, lipid peroxidation, fat accumulation in the hepatocytes, hyperleptinaemia, increased TNFα production and impaired expression of PPARγ receptors. Liver cell-related steatosis induces fibrosis progression also through ROS accumulation. Hyperleptinaemia with insulin resistance may play a role in the activation of hepatic stellate cells and fibrosis progression. In insulin resistance the TNFα production is enhanced in patients with hepatitis C and the increased level of TNFα initiates the fibrosis progression, owing to their ability to activate HSC and promote collagen deposits. Moreover, TNFα may inhibit PPARγ activity. An impaired expression of PPARγ receptors was found in patients with hepatitis C. PPARγ agonists inhibit inflammation and fibrosis progression by blocking the activation of the redox-sensitive transcription factor NF-κB and TGFβ1 [452].


The presence of steatosis not only significantly influences the natural history of patients with chronic hepatitis C, but the anti-viral response in these cases is highly decreased. While the sustained virological response is 60% of patients with hepatitis C infection without liver steatosis after 1 year peginterferon-alpha plus ribavirin treatment, this effect is only 30% with liver steatosis in HCV infection with genotype 1. Hepatic steatosis is a high risk factor for reduced response to anti-viral treatment and for evolution towards fibrosis. Obesity and fibrosis represent major therapeutic targets, in association with standard anti-viral regimes, like insulin-sensitizing drugs and free radical scavengers (silymarin, ursodeoxycholic acid, metadoxine); furthermore, the life mode with weight loss can help in therapy efficiency [447,453]. Body-weight reduction and hepatoprotective drugs might have increased the effectivity of combined peginterferon and ribavirin treatment, and thus the sustained virological response.


Alcoholic liver disease


Both acute and chronic alcohol consumption enhances the production of ROS, with the peroxidation of lipids, proteins and DNA. The mechanism by which alcohol causes cell injury is very similar to those observed in non-alcoholic steatohepatitis. Many pathways have been demonstrated in the literature for the alcohol effect, like the oxidative stress, acetaldehyde production, mitochondrial alterations, membrane injury, apoptosis, ethanol-induced hypoxia, effects on the immune system and altered cytokine production, increased endotoxin levels and activation of Kupffer cells, mobilization of iron, changes in the antioxidant defence, particularly mitochondrial glutathione (GSH), one electron oxidation of ethanol to 1-hydroxy-ethyl radical and induction of CYP2E1. These pathways are not exclusive of one another and it is likely that many systems contribute to the ability of ethanol to induce a state of oxidative stress [447,453,454].


Hepatocellular carcinoma


Hepatocellular carcinoma can develop in all kind of chronic liver diseases. The connections of the different factors are shown in Figure 12. In NAFLD the possible follow-up of the pathogenetic trends is: increased fatty acid fluxus, the increased fatty acid content in the liver (VLDL over-production, dyslipidaemia), advanced oxidation and peroxidation in fatty acids, highly increased free radical production (insufficient antioxidant capacity), flow out of inflammatory and immune reactive mediators (the changes in transcription and translation helping the progression of fibrosis) and finally the carcinogenesis.


In conclusion, oxidative stress plays a very important role in most chronic liver diseases, mainly in alcoholic and non-alcoholic steatohepatitis and liver cirrhosis, furthermore in chronic viral hepatitis, especially in chronic hepatitis C as well as in primary hepatocellular cancer (HCC). The diagnostic biomarkers to the clinical praxis can be seen in Table III.



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Evolutionary patterns in production of saturated and unsaturated fats--jk

 

Evolution operates to maximize survival, and thus the type of energy storage is balanced by costs.  For a variety of reasons animals and plants use carbohydrates and fats for energy.  Major factors for which is stored include durability, ease of conversion to the energy molecule ATP, bulk of material stored, and energy expended in their synthesis. 

 

So why do animals store fats?  In the form of glycogen, carbohydrates are six times as bulky per calorie of energy; thus fats offer a survival advantage over glycogen.  But for plants they don’t move, thus carbohydrates are the preferred source of energy storage, except for seeds where size matters.  Secondly, most insects prefer for food carbohydrates thus reducing the number of seeds lost to insects.

 

So why animals make and store saturated fats.  They are stable; i.e., they are not subject to rancidity, while polyunsaturated fats have the highest rate and monounsaturated a modest rate.  The rate of oxidation increases with number of double bonds.  Just like the unnatural trans-fats, rancid fats cannot be metabolized for energy; thus they clog up cells.  Rancid and trans-fats have major negative health consequences including that they are atherogenic. Animals are long lived, and the damage is cumulative, thus saturated fats provide a survival advantage over polyunsaturated fats. Scientists have demonstrated that saturated fats are much better for you than unsaturated fats. But what we are told repeatedly about fats is the opposite to what has been convincingly demonstrated. 

 

So why do we hear from the opinion leaders and government that polyunsaturated fats are better than saturated fats?    The lie is a product of tobacco science and corporate influence.  It is the manufactured foods and grain producing industries that promote plant derived oils and a high sugar diet.  Prof Miller accurately summarizes how tobacco science has come to dominate.  Watch his graphically entertaining lecture to an audience of physicians on YouTube.  The voice and financial clout of corporations follows the pattern of tobacco ethics, which operates counter to the public’s best interest.  And it gets worse.  Eating less fat entails eating more carbs for energy. Another chorus of scientist has gone public about the health disaster caused by the Western diet which includes in the U.S. an average of over 150 pounds of sugar per year per person.  Yet the evidence showing health harm by the combo of sugar and refined carbs has been by industries KOLs, government regulators, and the corporate media.      

 

So why for their seeds do plants make mostly make polyunsaturated fats (with the exception of trees)?  Saturated fats require more energy to produce, thus under certain conditions they are favored.  Most seeds will under normal moist condition germinate only during the first year or two.  These plants are short lived compared to trees.  With trees their long life entails much different evolutionary forces:  the number of oak trees is far less than for corn and soya bean plants, and the replacement rate is in decades versus a year.  The survival pressures for trees entails that their seeds need to survival for years.  Thus trees make the more stable saturated and monounsaturated fats for their seeds.  This is why cocoanuts make a high level of saturated, there seeds are relatively long live, while plants such as soya beans, sunflowers, and canola make mostly polyunsaturated fats, their seeds are short live, and thus oxidation of the oil in the seed do not have major effect upon germination.  The coconut will germinate years later. 


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