Plasma Oxylipins Levels in Nonalcoholic Fatty Liver Disease

Li, Qian; Rempel, Julia D.; Ball, T. Blake; Aukema, Harold M.; Minuk, Gerald Y.

doi:10.1007/s10620-020-06095-8

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…These results could indicate the enhanced activity of COX and LOX enzymes in the severe stage of NAFLD. Similar trends for most oxylipins derived from AA have been described comparing NAFLD subjects to healthy controls [ 52 ] and in NASH patients compared to NAFLD patients [ 7 , 28 ], evidencing the associations between the activation of LOX pathways and the progression of the disease to NASH. On the contrary, oxylipins derived from docosahexaenoic acid (DHA) through the LOX pathways, such as 17DoHE and RvD2, are present in the plasma of all patients at a similar concentration, although MaR1 plasma levels, also derived from DHA, are increased in severe NAFLD patients compared to the other NAFLD stages.…”

Section: Discussionsupporting

confidence: 74%

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

et al. 2023

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Hepatic fat accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD). Our aim was to determine the plasma levels of oxylipins, free polyunsaturated fatty acids (PUFA) and markers of lipid peroxidation in patients with NAFLD in progressive stages of the pathology. Ninety 40–60-year-old adults diagnosed with metabolic syndrome were distributed in without, mild, moderate or severe NAFLD stages. The free PUFA and oxylipin plasma levels were determined by the UHPLC–MS/MS system. The plasma levels of oxylipins produced by cyclooxygenases, lipoxygenases and cytochrome P450, such as prostaglandin 2α (PGF2α), lipoxinB4 and maresin-1, were higher in severe NAFLD patients, pointing to the coexistence of both inflammation and resolution processes. The plasma levels of the saturated oxylipins 16-hydroxyl-palmitate and 3-hydroxyl-myristate were also higher in the severe NAFLD patients, suggesting a dysregulation of oxidation of fatty acids. The plasma 12-hydroxyl-estearate (12HEST) levels in severe NAFLD were higher than in the other stages, indicating that the hydroxylation of saturated fatty acid produced by reactive oxygen species is more present in this severe stage of NAFLD. The plasma levels of 12HEST and PGF2α are potential candidate biomarkers for diagnosing NAFLD vs. non-NAFLD. In conclusion, the NAFLD progression can be monitored by measuring the plasma levels of free PUFA and oxylipins characterizing the different NAFLD stages or the absence of this disease in metabolic syndrome patients.

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Section: Discussionsupporting

confidence: 74%

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

et al. 2023

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“…Under oxidative stress, PUFAs can also undergo auto-oxidation to form alcohols, ketones, hydroperoxides [11]. Previous studies reported higher LOX and auto-oxidation metabolites in NAFL and increased AA metabolites via LOX with the progression to NASH [18,22,23,41]. In our results, compared to control groups, NAFL and NASH in both ethnicities presented higher alcohols and ketones derived from C18-PUFAs, indicating an upregulated LOX pathway(s).…”

Section: Discussionsupporting

confidence: 64%

Plasma Oxylipin Profile Discriminates Ethnicities in Subjects with Non-Alcoholic Steatohepatitis: An Exploratory Analysis

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) is a common liver pathology that includes steatosis, or non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH). Without a clear pathophysiological mechanism, it affects Hispanics disproportionately compared to other ethnicities. Polyunsaturated fatty acids (PUFAs) and inflammatory lipid mediators including oxylipin (OXL) and endocannabinoid (eCB) are altered in NAFLD and thought to contribute to its pathogenesis. However, the existence of ethnicity-related differences is not clear. We employed targeted lipidomic profiling for plasma PUFAs, non-esterified OXLs and eCBs in White Hispanics (HIS, n = 10) and Caucasians (CAU, n = 8) with biopsy-confirmed NAFL, compared with healthy control subjects (HC; n = 14 HIS; n = 8 CAU). NAFLD was associated with diminished long chain PUFA in HIS, independent of histological severity. Differences in plasma OXLs and eCBs characterized ethnicities in NASH, with lower arachidonic acid derived OXLs observed in HIS. The secondary analysis comparing ethnicities within NASH (n = 12 HIS; n = 17 CAU), confirms these ethnicity-related differences and suggests lower lipoxygenase(s) and higher soluble epoxide hydrolase(s) activities in HIS compared to CAU. While causes are not clear, these lipidomic differences might be with implications for NAFLD severity and are worth further investigation. We provide preliminary data indicating ethnicity-specific lipidomic signature characterizes NASH which requires further validation.

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“…The effects of fluoxetine to induce lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d‐PGJ 2 , a PPARG ligand. Future studies should aim to investigate how other arachidonic acid metabolites might also be involved in fluoxetine‐induced lipid accumulation and inflammatory processes involved in NAFLD (Li et al, 2020; Maciejewska et al, 2015; Marchix et al, 2020; Wang et al, 2021). An assessment of targets of intervention for the treatment and prevention of SSRI‐induced hepatic lipid accumulation is also warranted, as it may prove useful in the prevention of subsequent inflammation, fibrosis, and even cirrhosis of the liver associated with severe NAFLD (Cholankeril et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ^12,14PGJ₂

Ayyash

Holloway

2021

J of Applied Toxicology

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Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as nonalcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ 12,14 PGJ 2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ 12,14 PGJ 2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ 2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.15-deoxy-Δ 12,14 PGJ 2 (15d-PGJ 2 ), fatty acid uptake, fluoxetine, non-alcoholic fatty liver disease (NAFLD), peroxisome proliferator-activated receptor gamma (PPARG), prostaglandin, prostaglandin-endoperoxide synthase 1 (PTGS1), prostaglandin-endoperoxide synthase 2 (PTGS2), selective serotonin reuptake inhibitor (SSRI), steatosis 1 | INTRODUCTION Major depressive disorder (MDD) is a prevalent and often recurrent illness affecting nearly 350 million individuals worldwide and is predicted to be the leading cause of disability by 2030 (Longfei et al., 2015; World Health Organization, 2017). A global burden of disease study saw a 49.86% increase in incident cases of depression worldwide from 1990 to 2017 (Liu et al., 2020), with the financial burden of MDD in 2010 exceeding USD 210.5 billion in the

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Plasma Oxylipins Levels in Nonalcoholic Fatty Liver Disease

Cited by 17 publications

References 26 publications

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

Plasma Oxylipin Profile Discriminates Ethnicities in Subjects with Non-Alcoholic Steatohepatitis: An Exploratory Analysis

Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ^12,14PGJ₂

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Plasma Oxylipins Levels in Nonalcoholic Fatty Liver Disease

Cited by 17 publications

References 26 publications

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

Plasma Oxylipin Profile Discriminates Ethnicities in Subjects with Non-Alcoholic Steatohepatitis: An Exploratory Analysis

Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ12,14PGJ2

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Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ^12,14PGJ₂