linoleic-acid and Liver-Diseases--Alcoholic

Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy-octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca(2+) levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-α, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol-mediated induction of plasminogen activator inhibitor-1, an important alcohol-induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD.

Topics: Animals; Binge Drinking; Caspase 3; Chemokine CCL2; Chemokine CXCL2; Disease Models, Animal; Ethanol; Hep G2 Cells; Humans; Inflammation; Interleukin-6; Ligands; Linoleic Acid; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; TRPV Cation Channels; Tumor Necrosis Factor-alpha

The purpose of our study is to determine if a relationship exists between the severity of injury in experimental alcoholic liver disease and hepatic levels of leukotriene B4, leukotriene C4 and lipid peroxide. Splague-Dawley rats were fed ethanol (46% of calories) with either safflower oil (SE) or beef oil (BE) (20% of calories) for 12 weeks. Control animals were fed isocaloric amounts of dextrose instead of ethanol with the same diets. The followings were evaluated in each group: hepatic levels of leukotriene B4, C4, lipid peroxide, and collagen-bound hydroxyl-proline, hepatic fatty acid composition, incorporation of 14C-L-proline into hydroxyproline of collagen protein by liver slice. Rats fed SE showed the most abundant accumulation of hepatic hydroxyproline and lipid peroxide. Hepatic leukotriene B4 and C4, hepatic levels of linoleic acid and arachidonic acid were also greater in rat livers from animals fed the SE diet. A strong positive correlation was seen between hepatic levels of leukotrien B4 as well as C4 and lipid peroxide. The hepatic level of lipid peroxide also correlated positively with hepatic levels of linoleic acid and arachidonic acid. Our study shows the importance of leukotriene derived from arachidonic acid cascade in the pathogenesis of experimental alcoholic liver disease.

Topics: Animals; Arachidonic Acids; Dietary Fats; Inflammation Mediators; Leukotriene B4; Leukotriene C4; Linoleic Acid; Lipid Peroxides; Liver; Liver Diseases, Alcoholic; Male; Plant Oils; Rats; Rats, Sprague-Dawley

Increasing evidence indicates the involvement of immune reactions in the pathogenesis of alcoholic liver disease. We have investigated whether ethanol-induced oxidative stress might contribute to immune response in alcoholics. Antibodies against human serum albumin modified by reaction with malondialdehyde (MDA), 4-hydroxynonenal (HNE), 2-hexenal, acrolein, methylglyoxal, and oxidized arachidonic and linoleic acids were measured by ELISA in 78 patients with alcoholic cirrhosis and/or hepatitis, 50 patients with nonalcoholic cirrhosis, 23 heavy drinkers with fatty liver, and 80 controls. Titers of IgG-recognizing epitopes derived from MDA, HNE, and oxidized fatty acids were significantly higher in alcoholic as compared to nonalcoholic cirrhotics or healthy controls. No differences were instead observed in the titers of IgG-recognizing acrolein-, 2-hexenal-, and methylglyoxal-modified albumin. Alcoholics showing high IgG titers to one adduct tended to have high titers to all the others. However, competition experiments showed that the antigens recognized were structurally unrelated. Anti-MDA and anti-HNE antibodies were significantly higher in cirrhotics with more severe disease as well as in heavy drinkers with cirrhosis or extensive fibrosis than in those with fatty liver only. We conclude that antigens derived from lipid peroxidation contribute to the development of immune responses associated with alcoholic liver disease.

Topics: Acrolein; Adult; Aged; Aldehydes; Arachidonic Acid; Ethanol; Female; Humans; Immunoglobulin G; Linoleic Acid; Lipid Peroxidation; Liver Diseases, Alcoholic; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Serum Albumin

Cytochrome P4502E1 (CYP2E1) induction by ethanol contributes to alcoholic liver disease and we found that a mixture of polyunsaturated phosphatidylcholines (PPC), which protects against alcohol-induced liver injury, also decreases CYP2E1. Since dilinoleoylphosphatidylcholine (DLPC) is the major component of PPC, we assessed here whether it is responsible for the protection of PPC by feeding rats for 8 weeks our liquid diet containing ethanol (36% of energy) or isocaloric carbohydrates, with either DLPC (1.5 g/1000 cal), PPC (3 g/1000 cal), or linoleate. CYP2E1 was assessed by Western blots and by two of its enzyme activities: the microsomal ethanol-oxidizing system (MEOS) and p-nitrophenolhydroxylase (PNP). With ethanol, CYP2E1 increased 10-fold, with corresponding rises in PNP and MEOS activities. Compared to linoleate, DLPC significantly decreased cytochrome b(5), total cytochromes P450, CYP2E1 content and its corresponding activities. DLPC decreases ethanol-induced CYP2E1 and should be considered for the prevention of alcoholic liver disease.

Topics: Animals; Blotting, Western; Body Weight; Cytochrome P-450 CYP2E1; Cytochromes b5; Diet; Down-Regulation; Enzyme Induction; Ethanol; Linoleic Acid; Liver; Liver Diseases, Alcoholic; Male; Microsomes, Liver; Organ Size; Phosphatidylcholines; Rats; Rats, Sprague-Dawley

Long-term ethanol consumption in laboratory animals is associated with histological alterations of liver cells and modifications of fatty acid metabolism.. The present study was aimed at investigating the effect of 1- and 2-month chronic treatment of rats with ethanol on the metabolism of two unsaturated (oleic and linoleic) fatty acids in liver and kidney microsomes, in relation to the CYP2E1 enzyme content in both tissues.. Rats were fed ethanol (14 g/Kg/d) or dextrose through a permanently implanted gastric cannula, as described in the intragastric feeding rat model for alcoholic liver disease (ALD). CYP2E1 level was immuno-quantified in both liver and kidney microsomes by Western blot, whereas fatty acid omega- and (omega-1)-hydroxylations were measured using HPLC and radiometric analytical methods.. One- and two-month ethanol treatment led to a 3- to 4-fold rise of the CYP2E1 protein in both liver and kidney microsomes. Oleic and linoleic acid (omega-1)-hydroxylations were increased (approximately 3-fold) in liver microsomes after one-month of ethanol administration, but surprisingly such a rise was not observed after a two-month treatment; on the other hand, no effect was observed on the omega-hydroxylations of these fatty acids. Furthermore, as previously described for lauric acid, ethanol intake did not significantly act on the kidney microsome capability to hydroxylate unsaturated fatty acids.. CYP2E1 is strongly inducible by ethanol and therefore accounts for the tolerance for this hepatotoxicant. Our results support the development of an adaptation process in the liver hydroxylating enzyme system, which occurs between one and two months of ethanol feeding. Although it is usually not appropriate to extrapolate animal findings to humans, rat and human CYP2E1s were observed to have comparable specificities and similar mechanisms of regulation. Thus, the present study allowed the acquirement of detailed information of CYP2E1 activity in patients with severe manifestations of ALD.

Topics: Adaptation, Physiological; Animals; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2E1; Disease Models, Animal; Drug Tolerance; Ethanol; Glucose; Hydroxylation; Kidney; Linoleic Acid; Liver Diseases, Alcoholic; Male; Microsomes; Microsomes, Liver; Oleic Acid; Rats; Rats, Wistar

Topics: Animals; Dietary Fats; Fats; Linoleic Acid; Linoleic Acids; Liver Diseases, Alcoholic; Plant Oils; Rats; Sunflower Oil

We had previously hypothesized that linoleic acid (LA) was essential for development of alcoholic induced liver injury in our rat model. Male Wistar rats were fed a nutritionally adequate diet (25% calories as fat) with ethanol (8-17 g/kg/day). The source of fat was tallow (0.7% LA), lard (2.5% LA) or tallow supplemented with linoleic acid (2.5%). Liver damage was followed monthly by obtaining blood for alanine aminotransferase assay and liver biopsy for assessment of morphologic changes. Enzyme and histologic changes (fatty liver, necrosis and inflammation) in the tallow-linoleic acid-ethanol fed animals were more severe than in the lard-ethanol group. The tallow ethanol group did not show any evidence of liver injury. Our results strongly support our hypothesis that LA is essential for development of alcoholic liver disease in our rat model.

Topics: Alanine Transaminase; Animals; Dietary Fats; Disease Models, Animal; Linoleic Acid; Linoleic Acids; Liver Diseases, Alcoholic; Male; Rats; Rats, Inbred Strains

The level of conjugated dienes (CD) in the serum, conjugated linoleic acid isomer in the phospholipid fraction [18:2(9, 11)], and the fatty acid profile in both the serum and in the separated lipid classes were analyzed in current and previous alcohol abusers and in patients with alcoholic liver disease. None of the subjects consumed alcohol for at least 2-3 days prior to blood collection for analysis of lipids. There was no significant difference in CD or in the absolute level of 18:2(9, 11) among the groups, whereas the 18:2(9, 11)/18:2(9, 12) molar ratio was significantly elevated in patients with liver disease. Fatty acid analysis of the whole plasma extract showed that the absolute level of arachidonic acid increased from 4.8 +/- 3.5 mg/dl (n = 9) in lifelong abstainers to 13.4 +/- 4.0 (n = 8) in current ethanol abusers, and its relative level (related to the total fatty acids) from 1.73 +/- 1.34 to 4.55 +/- 1.01 in the same groups. An increased proportion of linoleic acid in the triglyceride and phospholipid fractions from current abusers and patients with liver disease was also found; the percentage of 18:2 in phospholipids increased from 5.4 +/- 5.0 (n = 8) in lifelong abstainers to 14.3 +/- 3.9 (n = 8) in current abusers and 12.7 +/- 2.2 (n = 10) in patients with liver disease. The percentage of 16:0 was significantly lower in the phospholipids of current abusers as compared to lifelong abstainers.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alcoholism; Arachidonic Acid; Arachidonic Acids; Fatty Acids; Humans; Linoleic Acid; Linoleic Acids; Liver Diseases, Alcoholic; Male; Middle Aged; Phospholipids