Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study

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.

Trial registration: ClinicalTrials.gov NCT00760513.

Figure 1

Consort diagram showing recruitment for the WELCOME sub-study and the numbers of subjects available for hepatic fatty acid metabolism and insulin sensitivity studies. See text for the reasons for withdrawal from the study.

Figure 2

Correlations between change in erythrocyte DHA (%) and change in fasting plasma VLDL-triacylglycerol (TG) concentrations (μmol/l) (a); change in erythrocyte DHA (%) and change in the fasting contribution (μmol/l) of DNL fatty acids to VLDL-TG (b); and change in erythrocyte DHA (%) and change in postprandial plasma [¹³C]3OHB concentrations (μmol/L) (c).