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

L Hodson, L Bhatia, E Scorletti, D E Smith, N C Jackson, F Shojaee-Moradie, M Umpleby, P C Calder, C D Byrne, L Hodson, L Bhatia, E Scorletti, D E Smith, N C Jackson, F Shojaee-Moradie, M Umpleby, P C Calder, C D Byrne

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
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
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).

References

    1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142: 1592–1609.
    1. Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28: 27–38.
    1. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 2008; 134: 1369–1375.
    1. Byrne CD. Dorothy Hodgkin Lecture 2012: non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management. Diabet Med 2012; 29: 1098–1107.
    1. McKenney JM, Sica D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy 2007; 27: 715–728.
    1. Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006; 49: 755–765.
    1. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology 2014; 60: 1211–1221.
    1. Cussons AJ, Watts GF, Mori TA, Stuckey BG. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J Clin Endocrinol Metab 2009; 94: 3842–3848.
    1. Spadaro L, Magliocco O, Spampinato D, Piro S, Oliveri C, Alagona C et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 2008; 40: 194–199.
    1. Galgani JE, Uauy RD, Aguirre CA, Diaz EO. Effect of the dietary fat quality on insulin sensitivity. Br J Nutr 2008; 100: 471–479.
    1. Janczyk W, Lebensztejn D, Wierzbicka-Rucinska A, Mazur A, Neuhoff-Murawska J, Matusik P et al. Omega-3 Fatty acids therapy in children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr 2015; 166: 1358–63 e1-3.
    1. Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42: 413–418.
    1. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Calder PC et al. Design and rationale of the WELCOME trial: a randomised, placebo controlled study to test the efficacy of purified long chainomega-3 fatty acid treatment in non-alcoholic fatty liver disease [corrected]. Contemp Clin Trials 2014; 37: 301–311.
    1. Browning LM, Walker CG, Mander AP, West AL, Madden J, Gambell JM et al. Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish. Am J Clin Nutr 2012; 96: 748–758.
    1. Shojaee-Moradie F, Jackson NC, Jones RH, Mallet AI, Hovorka R, Umpleby AM. Quantitative measurement of 3-O-methyl-D-glucose by gas chromatography-mass spectrometry as a measure of glucose transport in vivo. J Mass Spectrom 1996; 31: 961–966.
    1. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214–E223.
    1. Steele R, Bishop JS, Dunn A, Altszuler N, Rathbeb I, Debodo RC. Inhibition by insulin of hepatic glucose production in the normal dog. Am J Physiol 1965; 208: 301–306.
    1. Finegood DT, Bergman RN, Vranic M. Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps. Diabetes 1988; 37: 1025–1034.
    1. Finegood DT, Bergman RN. Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. Am J Physiol 1983; 244: E472–E479.
    1. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462–1470.
    1. Pramfalk C, Pavlides M, Banerjee R, McNeil CA, Neubauer S, Karpe F et al. Sex-specific differences in hepatic fat oxidation and synthesis may explain the higher propensity for NAFLD in men. J Clin Endocrinol Metab 2015; 100: 4425–4433.
    1. Heath RB, Karpe F, Milne RW, Burdge GC, Wootton SA, Frayn KN. Selective partitioning of dietary fatty acids into the VLDL TG pool in the early postprandial period. J Lipid Res 2003; 44: 2065–2072.
    1. Hodson L, Bickerton AS, McQuaid SE, Roberts R, Karpe F, Frayn KN et al. The contribution of splanchnic fat to VLDL triglyceride is greater in insulin-resistant than insulin-sensitive men and women: studies in the postprandial state. Diabetes 2007; 56: 2433–2441.
    1. Santoro N, Caprio S, Pierpont B, Van Name M, Savoye M, Parks EJ. Hepatic de novo lipogenesis in obese youth is modulated by a common variant in the GCKR gene. J Clin Endocrinol Metab 2015; 100: E1125–E1132.
    1. Elizondo A, Araya J, Rodrigo R, Poniachik J, Csendes A, Maluenda F et al. Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients. Obesity (Silver Spring) 2007; 15: 24–31.
    1. Elizondo A, Araya J, Rodrigo R, Signorini C, Sgherri C, Comporti M et al. Effects of weight loss on liver and erythrocyte polyunsaturated fatty acid pattern and oxidative stress status in obese patients with non-alcoholic fatty liver disease. Biol Res 2008; 41: 59–68.
    1. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002; 87: 3023–3028.
    1. Bordin P, Bodamer OA, Venkatesan S, Gray RM, Bannister PA, Halliday D. Effects of fish oil supplementation on apolipoprotein B100 production and lipoprotein metabolism in normolipidaemic males. Eur J Clin Nutr 1998; 52: 104–109.
    1. Nestel PJ, Connor WE, Reardon MF, Connor S, Wong S, Boston R. Suppression by diets rich in fish oil of very low density lipoprotein production in man. J Clin Invest 1984; 74: 82–89.
    1. Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y et al. Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. J Biol Chem 2010; 285: 11681–11691.
    1. Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R et al. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol 2015; 49: 137–144.
    1. Scorletti E, West AL, Bhatia L, Hoile SP, McCormick KG, Burdge GC et al. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: results from the WELCOME trial. J Hepatol 2015; 63: 1476–1483.
    1. Allaire J, Couture P, Leclerc M, Charest A, Marin J, Lepine MC et al. A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the comparing EPA to DHA (ComparED) Study. Am J Clin Nutr 2016; 104: 280–287.
    1. Perdomo L, Beneit N, Otero YF, Escribano O, Diaz-Castroverde S, Gomez-Hernandez A et al. Protective role of oleic acid against cardiovascular insulin resistance and in the early and late cellular atherosclerotic process. Cardiovasc Diabetol 2015; 14: 75.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe