linoleic-acid and 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. Maintaining an optimally low n-6/n-3 PUFA ratio is linked to prevention of the development of several diseases, including nonalcoholic fatty liver disease (NAFLD) that is characterized by depletion of PUFA promoting hepatic steatosis and inflammation. In this context, supplementation with n-3 PUFA revealed significant lowering of hepatic steatosis in obese patients, whereas prevention of fatty liver by high-fat diet in mice is observed in n-3 PUFA and hydroxytyrosol co-administration. The aim of this work is to review the role of nutritional status and nutrient availability on markers of PUFA biosynthesis. In addition, the impact of oxidative stress developed as a result of NAFLD, a redox imbalance that may alter the expression and activity of the enzymes involved, and diminished n-3 PUFA levels by free-radical dependent peroxidation processes will be discussed.

Topics: Animals; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Liver; Mice; Non-alcoholic Fatty Liver Disease; Nutritional Status; Oxidative Stress

Pentoxifylline (PTX) improved the histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical-mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH. Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadienoic acids (HODEs), oxo-octadecadienoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial. Therapy with PTX resulted in significant decreases in 9-HODE and 13-oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in nonalcoholic fatty liver disease. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis and between the decrease in HETEs and improved lobular inflammation.. Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical-mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH.

Topics: Adult; Biopsy, Needle; Blood Chemical Analysis; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Fatty Liver; Female; Follow-Up Studies; Humans; Immunohistochemistry; Insulin Resistance; Linoleic Acid; Lipid Metabolism; Lipid Peroxidation; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Patient Selection; Pentoxifylline; Prospective Studies; Reference Values; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome

Increased uptake of fat, such as through the ingestion of high fat diet (HFD), can lead to fatty liver diseases and metabolic syndrome. It is not clear whether certain fatty acids may be more pathogenic than others to the liver. Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in the Western diet and its excessive consumption can lead to increased lipid peroxidation. We hypothesized that a high level of LA in HFD will contribute significantly to the hepatic steatosis and injury, whereas vitamin E (VIT-E) may reverse the effects from LA by inhibiting lipid peroxidation. To test this hypothesis, we fed mice with the following diets for 20 weeks: a standard low-fat diet (CHOW), HFD with a low level of LA (LOW-LA, 1% of energy from LA), HFD with a high level of LA (HI-LA, 8% of energy from LA), or HI-LA diet with VIT-E supplement (HI-LA + VIT-E). We found that the HI-LA diet resulted in more body weight gain, larger adipocyte area, and higher serum levels of triglycerides (TG) and free fatty acids (FFA) relative to the CHOW and LOW-LA diets. In mice fed with the HI-LA diet, severer hepatic steatosis was seen with higher levels of hepatic TG and FFA. Expression of genes related to lipid metabolism was altered in the liver by HI-LA diet, including fibroblast growth factor 21 (Fgf21), cluster of differentiation 36 (Cd36), stearoyl-CoA desaturase 1 (Scd1), and acyl-CoA oxidase 1 (Acox1). Liver injury, inflammation and fibrotic response were all enhanced in mice fed with the HI-LA diet when compared with the LOW-LA diet. Notably, addition of VIT-E supplement, which restores the proper VIT-E/PUFA ratio, significantly reduced the detrimental effects of the high level of LA. Taken together, our results suggest that a high level of LA and a low ratio of VIT-E/PUFA in HFD can contribute significantly to metabolic abnormalities and hepatic injury.

Topics: Animals; Diet, High-Fat; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Linoleic Acid; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Triglycerides; Vitamin E

The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β-induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.

Topics: Animals; Diet, High-Fat; Fibrosis; Gastrointestinal Microbiome; Hepatic Stellate Cells; Humans; Linoleic Acid; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pioglitazone; Transforming Growth Factor beta

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver diseases worldwide, and lifestyle and diet are significant factors in its development. Recent studies have suggested that dietary fat quality is associated with the development of NAFLD.. Our purpose was to investigate the cross-sectional and longitudinal associations of serum n-3 (ω-3) and n-6 (ω-6) PUFAs with NAFLD among middle-aged and older men and women from eastern Finland. We also investigated the associations of estimated Δ5-desaturase and Δ6-desaturase activities, enzymes involved in PUFA metabolism, with NAFLD.. After exclusions, the cross-sectional analyses included 1533 men examined in 1984-1989 and 674 men and 870 women examined in 1998-2001 in the Kuopio Ischaemic Heart Disease Risk Factor Study. The longitudinal analyses included 520 men examined in 1991-1993 and 301 men and 466 women examined in 2005-2008. Fatty liver index (FLI) was used as a surrogate for NAFLD. Hepatic steatosis was defined as FLI >60. ANCOVA and logistic regression were used for analyses.. In the longitudinal analyses, participants with higher serum concentrations of total n-6 PUFA and linoleic acid, the major n-6 PUFA, had markedly lower FLI and lower odds for hepatic steatosis (e.g., odds ratios for incident hepatic steatosis in the highest compared with lowest quartiles were ≤0.41), whereas serum γ-linolenic acid concentration was associated with a higher FLI and higher odds for hepatic steatosis. The associations with the other PUFAs were generally weaker and nonsignificant. In the cross-sectional analyses, also the long-chain n-3 PUFAs had inverse associations. In most analyses, high estimated Δ5-desaturase activity was associated with lower risk and high estimated Δ6-desaturase activity with higher risk for NAFLD.. In middle-aged and older Finnish adults, higher serum concentrations of total n-6 PUFAs and linoleic acid were associated with lower odds for future NAFLD.

Topics: Adult; Aged; Cross-Sectional Studies; Fatty Acid Desaturases; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Humans; Incidence; Linoleic Acid; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Prevalence; Prospective Studies

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent, chronic liver diseases worldwide and currently has no specific therapy. Our previous study indicated the anti-NAFLD effect of Macrocybe gigantea (Massee) Pegler & Lodge in high-fat diet-fed animals. This study aimed to isolate and identify the active hepatoprotective constituents from M. gigantea using fatty acid induced steatotic HepG2 cells as in vitro model. The effect of the test materials on the viability of HepG2 cells was analyzed using MTT assay. The HepG2 cells were treated with a mixture of palmitate-oleate to induce steatosis; after 24 h of treatment with the test materials, the intracellular lipid content was estimated using Oil Red O staining. The levels of transaminases were also estimated in the spent media. Bioassay-guided isolation of hepatoprotective constituents from M. gigantea yielded two compounds viz., ergosterol and linoleic acid; their structures were confirmed using spectroscopic data. Among these two compounds, ergosterol significantly lowered the levels of intracellular triglyceride content of fatty acid induced HepG2 cells; it also lowered the leakage of transaminases. The reductions caused by linoleic acid were not statistically significant at the tested concentrations. Detailed investigations on efficacy and safety of these compounds and M. gigantea might yield some useful leads for the management of NAFLD.

Topics: Agaricales; Animals; Diet, High-Fat; Ergosterol; Fatty Acids; Hep G2 Cells; Humans; Linoleic Acid; Liver; Non-alcoholic Fatty Liver Disease; Transaminases

Obesity is a major cause of non-alcoholic fatty liver disease (NAFLD). NAFLD is an epidemic affecting nearly 34% of the adult population in the US. As a chronic inflammatory disease, NAFLD influences the immune system by dysregulating T-cell activity. Remedies for the adverse effects on the immune system are urgently needed. We studied Theaphenon E (TE), a standardized formulation of green tea extract, on the adverse effects of NAFLD in C57BL/6J mice fed a high fat diet (HFD).. Mice received HFD, low fat diet (LFD) or HFD+2% TE for 35 weeks. Hepatic lipid accumulation, cell proliferation, apoptosis and CD4+T lymphocytes were measured throughout the bioassay. The hepatic composition of fatty acids was determined. The effects of epigallocatechin gallate (EGCG) metabolites on lipid accumulation in mouse and primary human liver cells were studied.. Unlike mice receiving HFD, mice on HFD+2% TE maintained normal liver to body weight ratios with low levels of alanine and aspartate aminotransferase (ALT and AST). Hepatic lipid accumulation was observed in HFD mice, accompanied by increased proliferation, reduced apoptosis and loss of CD4+ T lymphocytes. TE significantly inhibited lipid accumulation, decreased proliferation, induced apoptosis and increased CD4+ T cell survival in HFD mice. It was found that the EGCG metabolite EGC-M3 reduced lipid accumulation in mouse and human hepatocytes. Linoleic acid showed the largest increase (2.5-fold) in livers of mice on a HFD and this increase was significantly suppressed by TE.. Livers of HFD-fed mice showed lipid accumulation, increased proliferation, reduced apoptosis, elevated linoleic acid and loss of CD4+ T cells. TE effectively ameliorated all of these adverse effects.

Topics: Animals; Apoptosis; Catechin; CD4-Positive T-Lymphocytes; Cell Proliferation; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Hepatocytes; Humans; Linoleic Acid; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide. As obesity and diabetes become more prevalent, the contribution of non-alcoholic fatty liver disease (NAFLD) to HCC is rising. Recently, we reported intrahepatic CD4

Topics: 3T3 Cells; Animals; Apoptosis; Carcinogenesis; Carcinoma, Hepatocellular; Carnitine O-Palmitoyltransferase; CD4-Positive T-Lymphocytes; Enzyme Inhibitors; Humans; Linoleic Acid; Liver Neoplasms; Mice; Mice, Inbred C57BL; Mitochondria; Models, Biological; Non-alcoholic Fatty Liver Disease; Perhexiline; PPAR alpha; Reactive Oxygen Species; Up-Regulation

Dietary supplementation with conjugated linoleic acid (CLA) has been proposed for weight management and to prevent gut inflammation. However, some animal studies suggest that supplementation with CLA leads to the development of nonalcoholic fatty liver disease. The aims of this study were to test the efficiency of CLA in preventing dextran sulfate sodium (DSS)-induced colitis, to analyze the effects of CLA in the liver function, and to access putative liver alterations upon CLA supplementation during colitis. So, C57BL/6 mice were supplemented for 3 weeks with either control diet (AIN-G) or 1% CLA-supplemented diet. CLA content in the diet and in the liver of mice fed CLA containing diet were accessed by gas chromatography. On the first day of the third week of dietary treatment, mice received ad libitum a 1.5%-2.5% DSS solution for 7 days. Disease activity index score was evaluated; colon and liver samples were stained by hematoxylin and eosin for histopathology analysis and lamina propria cells were extracted to access the profile of innate cell infiltrate. Metabolic alterations before and after colitis induction were accessed by an open calorimetric circuit. Serum glucose, cholesterol, triglycerides and alanine aminotransaminase were measured; the content of fat in liver and feces was also accessed. CLA prevented weight loss, histopathologic and macroscopic signs of colitis, and inflammatory infiltration. Mice fed CLA-supplemented without colitis induction diet developed steatosis, which was prevented in mice with colitis probably due to the higher lipid consumption as energy during gut inflammation. This result suggests that CLA is safe for use during gut inflammation but not at steady-state conditions.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Dextran Sulfate; Dietary Supplements; Female; Immunity, Innate; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease

The aim of this study was to determine the optimal weighting factor (WF) for precise quantification using six-point interference Dixon fat percentage imaging by analyzing changes in WFs of fatty acid metabolites (FMs) in high-fat-induced fatty liver disease rat model.. Individual FM-related WFs were calculated based on concentration ratios of integrated areas of seven peak FMs with four phantom series. Ten 8-week-old male Sprague-Dawley rats were used for baseline quantification of fat in liver magnetic resonance imaging or magnetic resonance spectroscopy data. These seven lipid metabolites were then quantitatively analyzed. Spearman test was used for correlation analysis of different lipid proton concentrations. The most accurate WF for six-point interference Dixon fat percentage imaging was then determined.. The seven lipid resonance WF values obtained from magnetic resonance spectroscopy data for three different oils (oleic, linoleic, and soybean) were different from each other. In lipid phantoms, except for the phantom containing oleic acid, changes in FP values were significantly different when WFs were changed in six-point interference Dixon fat percentage image. The seven lipid resonance WF values for the nonalcoholic fatty liver animal model were different from human subcutaneous adipose tissue lipid WF values.. WF affected the calculation of six-point interference Dixon-based fat percentage imaging value in phantom experiment. If WF of liver parenchyma FM which is specific to each liver disease is applied, the accuracy of six-point interference Dixon fat percentage imaging can be further increased.

Topics: Adipose Tissue; Animals; Disease Models, Animal; Linoleic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Non-alcoholic Fatty Liver Disease; Oleic Acid; Phantoms, Imaging; Rats; Rats, Sprague-Dawley; Soybean Oil

The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties.. This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model.. The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages.. Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.

Topics: Animals; Antioxidants; CD4-Positive T-Lymphocytes; Curcumin; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Hepatocytes; Humans; Leptin; Linoleic Acid; Liver; Mice; Non-alcoholic Fatty Liver Disease; Reactive Oxygen Species

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Case-Control Studies; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Choline; Diet; Disease Models, Animal; Genes, myc; Hepatocytes; Humans; Linoleic Acid; Lipid Metabolism; Liver; Liver Neoplasms; Male; Methionine; Mice; Mice, Inbred C57BL; Mitochondria; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Reactive Oxygen Species

Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to define the circulating profile of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels reflect histological changes in the liver. The levels of multiple structurally specific oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9- and 13-HODEs and 9- and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were significantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (inflammation, fibrosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold (P < 0.0001) more likely to have NASH than those with low levels (bottom tertile). Collectively, these findings support a key role for free radical-mediated linoleic acid oxidation in human NASH and define a risk score, oxNASH, for noninvasive detection of the presence of NASH.

Topics: Cohort Studies; Fatty Acids, Unsaturated; Fatty Liver; Humans; Hydroxyeicosatetraenoic Acids; Linoleic Acid; Lipid Metabolism; Lipids; Non-alcoholic Fatty Liver Disease; Spectrometry, Mass, Electrospray Ionization