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Plasma Oxylipins Levels in Nonalcoholic Fatty Liver Disease

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Abstract

Background

Activation of innate immunity by gut-derived immunogens such as lipopolysaccharides (LPS) may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether NAFLD-associated lipid disturbances and polyunsaturated fatty acid (PUFA) metabolism in particular contribute to heightened innate immunity, remains to be determined.

Objective

To determine if oxylipins, metabolic products of PUFA metabolism, enhance innate immune reactivity alone and/or following exposure to LPS.

Methods

Plasma and peripheral blood mononuclear cells (PBMC) were collected from 35 NAFLD patients and 8 healthy controls. Oxylipin levels were documented by HPLC–MS/MS, cytokines (IL-1, IL-6, IL-10, and TNF-α) by ELISA, and chemokine receptors (CCR1 and CCR2) by flow cytometry.

Results

Mean plasma levels of four pro-inflammatory oxylipins (Tetranor 12-HETE, 20-HETE, 8-HETrE, and 7-HDoHE) were significantly elevated in NAFLD patients compared to healthy controls. However, the levels did not correlate with the severity of liver injury as reflected by serum aminotransferases, ck18M30, and Fib-4 determinations. In vitro, 20-HETE (0.01–100 nM), the plasma oxylipin with the most significantly elevated plasma levels, did not alter NAFLD or control PBMC cytokine release or enhance the increases in cytokine release following 24 h of LPS exposure. Similarly, 20-HETE alone did not alter PBMC CCR1 or CCR2 expression or LPS-induced downregulation of these receptors.

Conclusions

Pro-inflammatory oxylipin levels are increased in NAFLD, but these metabolites do not appear to drive short-term direct or LPS-induced increases in PBMC cytokine release or chemotaxis.

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Abbreviations

LPS:

Lipopolysaccharides

NAFLD:

Nonalcoholic fatty liver disease

PUFA:

Polyunsaturated fatty acid

PBMC:

Peripheral blood mononuclear cells

AA:

Arachidonic acid

COX:

Cyclooxygenases

LOX:

Lipoxygenases

CYP:

Cytochrome P450

CCR:

Chemokine receptors

HC:

Healthy controls

ELISAs:

Enzyme-linked immune absorbent assays

FMO:

Fluorochrome minus one condition

LA:

Linoleic acid

γLA:

γ-linolenic acid

ALA:

α-linolenic acid

EPA:

Eicosapentaenoic acid

DHA:

Docosahexaenoic acid

NASH:

Nonalcoholic steatohepatitis

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Acknowledgments

The authors wish to thank Ms R. Vizniak for her prompt and accurate typing of the manuscript.

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Authors and Affiliations

  1. Morberg Family Chair in Hepatology, Section of Hepatology, Department of Medicine, John Buhler Research Centre, University of Manitoba, 715 McDermot Ave., Winnipeg, MB, R3E 3P4, Canada

    Qian Li, Julia D. Rempel & Gerald Y. Minuk

  2. Medical Microbiology and Immunology, University of Manitoba, Winnipeg, MB, Canada

    Terry B. Ball

  3. Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada

    Harold Aukema

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  1. Qian Li
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  2. Julia D. Rempel
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Correspondence to Gerald Y. Minuk.

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Li, Q., Rempel, J.D., Ball, T.B. et al. Plasma Oxylipins Levels in Nonalcoholic Fatty Liver Disease. Dig Dis Sci 65, 3605–3613 (2020). https://doi.org/10.1007/s10620-020-06095-8

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