A Lipidomic Analysis of Docosahexaenoic Acid (22:6, ω3) Mediated Attenuation of Western Diet Induced Nonalcoholic Steatohepatitis in Male Ldlr -/- Mice.

Manuel García-Jaramillo,Kelli A Lytle,Donald B Jump,Melinda H Spooner

doi:10.3390/metabo9110252

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and primary hepatocellular cancer (HCC). Obesity and type 2 diabetes mellitus (T2DM) are strongly associated with NAFLD, and the western diet (WD) is a major contributor to the onset and progression of these chronic diseases. Our aim was to use a lipidomic approach to identify potential lipid mediators of diet-induced NASH. We previously used a preclinical mouse (low density lipoprotein receptor null mouse, Ldlr -/-) model to assess transcriptomic mechanisms linked to WD-induced NASH and docosahexaenoic acid (DHA, 22:6, ω3)-mediated remission of NASH. This report used livers from the previous study to carry out ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography coupled with dynamic multi-reaction monitoring (HPLC-dMRM) to assess the impact of the WD and DHA on hepatic membrane lipid and oxylipin composition, respectively. Feeding mice the WD increased hepatic saturated and monounsaturated fatty acids and arachidonic acid (ARA, 20:4, ω6) in membrane lipids and suppressed ω3 polyunsaturated fatty acids (PUFA) in membrane lipids and ω3 PUFA-derived anti-inflammatory oxylipins. Supplementing the WD with DHA lowered hepatic ARA in membrane lipids and ARA-derived oxylipins and significantly increased hepatic DHA and its metabolites in membrane lipids, as well as C20–22 ω3 PUFA-derived oxylipins. NASH markers of inflammation and fibrosis were inversely associated with hepatic C20–22 ω3 PUFA-derived Cyp2C- and Cyp2J-generated anti-inflammatory oxylipins (false discovery rate adjusted p-value; q ≤ 0.026). Our findings suggest that dietary DHA promoted partial remission of WD-induced NASH, at least in part, by lowering hepatic pro-inflammatory oxylipins derived from ARA and increasing hepatic anti-inflammatory oxylipins derived from C20–22 ω3 PUFA.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic fatty liver disease worldwide [1,2,3] and is defined as excessive neutral lipid deposition in the liver in individuals who consume little or no alcohol [4,5]
We previously reported that feeding female Ldlr -/- mice fed the western diet (WD) decreased hepatic oxylipins derived from linoleic acid (LA, 18:2, ω6), but increased hepatic oxylipins derived from arachidonic acid (ARA, 20:4, ω6) [60]
Oxylipins highlighted in blue represent oxylipins that were quantified published bygas

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic fatty liver disease worldwide [1,2,3] and is defined as excessive neutral lipid deposition in the liver in individuals who consume little or no alcohol [4,5]. Obesity and type 2 diabetes mellitus (T2DM) are strongly. Based on estimates from the Centers for Disease Control, ~93 million adults [10] and. ~14 million children [11] in the US are obese. As such, both obese children and adults are at risk of developing NAFLD [12]. Diet, genetics, and endocrine status contribute to the onset of NAFLD and its progression to nonalcoholic steatohepatitis (NASH), cirrhosis, and primary hepatocellular cancer (HCC) [7,13]. NAFLD is a risk factor for cardiovascular disease [14,15,16]. The top four risk factors for NAFLD are obesity, T2DM, dyslipidemia, and metabolic syndrome [17,18]

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