Abstract
Background/Objective:Treatment of subjects with non-alcoholic fatty liver disease (NAFLD) with omega-3 polyunsaturated fatty acids (FAs) suggests high levels of docosahexaenoic acid (DHA) tissue enrichment decrease liver fat content. We assessed whether changes in erythrocyte DHA enrichment (as a surrogate marker of changes in tissue enrichment) were associated with alterations in hepatic de novo lipogenesis (DNL), postprandial FA partitioning and hepatic and peripheral insulin sensitivity in a sub-study of the WELCOME trial (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD (non-alcoholic fatty liver disease) with OMacor thErapy).Subjects/Methods:Sixteen participants were randomised to 4 g/day EPA+DHA (n=8) or placebo (n=8) for 15–18 months and underwent pre- and post-intervention measurements. Fasting and postprandial hepatic FA metabolism was assessed using metabolic substrates labelled with stable-isotope tracers (2H2O and [U13C]palmitate). Insulin sensitivity was measured by a stepped hyperinsulinaemic-euglycaemic clamp using deuterated glucose. Participants were stratified according to change in DHA erythrocyte enrichment (< or ⩾2% post intervention).Results:Nine participants were stratified to DHA⩾2% (eight randomised to EPA+DHA and one to placebo) and seven to the DHA<2% group (all placebo). Compared with individuals with erythrocyte <2% change in DHA abundance, those with ⩾2% enrichment had significant improvements in hepatic insulin sensitivity, reduced fasting and postprandial plasma triglyceride concentrations, decreased fasting hepatic DNL, as well as greater appearance of 13C from dietary fat into plasma 3-hydroxybutyrate (all P<0.05).Conclusions:The findings from our pilot study indicate that individuals who achieved a change in erythrocyte DHA enrichment ⩾2% show favourable changes in hepatic FA metabolism and insulin sensitivity, which may contribute to decreasing hepatic fat content.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver fatrelated conditions that increase risk of chronic metabolic disease such as type 2 diabetes and cardiovascular disease, with obesity and insulin resistance (IR) being well-documented risk factors.[1]
We report here data demonstrating that individuals with NAFLD, who have an increase in erythrocyte docosahexaenoic acid (DHA) enrichment of ⩾ 2% through treatment with omega-3 fatty acids (FAs), show favourable changes in both hepatic insulin sensitivity and hepatic FA metabolism
Erythrocyte DHA enrichment ⩾ 2% was associated with a nonsignificant (26%) decrease in liver fat content, hepatic de novo lipogenesis (DNL) significantly decreased while hepatic FA oxidation and hepatic insulin sensitivity significantly increased
Summary
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver fatrelated conditions that increase risk of chronic metabolic disease such as type 2 diabetes and cardiovascular disease, with obesity and insulin resistance (IR) being well-documented risk factors.[1]. High-dose omega-3 FA (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are a licensed treatment to reduce plasma TG concentrations.[5] As NAFLD is associated with an overproduction of very low-density lipoprotein (VLDL)-TG,[6] it is plausible that one contributor to the hypotriglyceridemic effect of omega-3 FA is through a lowering of liver fat content. In addition to potentially lowering liver fat, short-term omega-3 FA treatment has been reported to improve whole-body insulin sensitivity.[8,9] the effects of omega-3 FA on insulin sensitivity in the context of NAFLD remains unclear, as some studies report neutral or negative results,[10,11] despite a concomitant reduction in NAFLD severity.[12]. The current study is a pre-specified sub-study of the WELCOME* randomised double-blind, placebo-controlled trial.[7,13] The aim of this pilot sub-study was to test if a pre-specified increase (⩾ 2%) in erythrocyte enrichment of DHA7,13 was associated with changes in hepatic FA synthesis, postprandial FA partitioning and hepatic and peripheral insulin sensitivity
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