Dietary macronutrient composition may affect hepatic liver content and its associated diseases, but the results from human intervention trials have been equivocal or underpowered. We aimed to assess the effects of dietary macronutrient composition on liver fat content by conducting a systematic review and meta-analysis of randomized controlled trials in adults. Four databases (PubMed, Embase, Web of Science, and COCHRANE Library) were systematically searched for trials with isocaloric diets evaluating the effect of dietary macronutrient composition (energy percentages of fat, carbohydrates, and protein, and their specific types) on liver fat content as assessed by magnetic resonance techniques, computed tomography or liver biopsy. Data on change in liver fat content were pooled by random or fixed-effects meta-analyses and expressed as standardized mean difference (SMD). We included 26 randomized controlled trials providing data for 32 comparisons on dietary macronutrient composition. Replacing dietary fat with carbohydrates did not result in changes in liver fat (12 comparisons, SMD 0.01 (95% CI −0.36; 0.37)). Unsaturated fat as compared with saturated fat reduced liver fat content (4 comparisons, SMD −0.80 (95% CI −1.09; −0.51)). Replacing carbohydrates with protein reduced liver fat content (5 comparisons, SMD −0.33 (95% CI −0.54; −0.12)). Our meta-analyses showed that replacing carbohydrates with total fat on liver fat content was not effective, while replacing carbohydrates with proteins and saturated fat with unsaturated fat was. More well-performed and well-described studies on the effect of types of carbohydrates and proteins on liver fat content are needed, especially studies comparing proteins with fats.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Relationship between liver fat content and lifestyle factors in adults with metabolic syndrome
Scientific Reports Open Access 19 October 2022
Ketone bodies: from enemy to friend and guardian angel
BMC Medicine Open Access 09 December 2021
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Data used in the manuscript, code book, and analytic code will be made available to editors upon request.
Petäjä EM, Yki-Järvinen H. Definitions of normal liver fat and the association of insulin sensitivity with acquired and genetic NAFLD—a systematic review. Int J Mol Sci. 2016;17:633.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124–31.
Haddad TM, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: a systematic review and meta-analysis. Diabetes Metab Syndrome. 2017;11:S209–16.
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–50.
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 Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.
Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care. 2018;41:372–82.
Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Digestive Liver Dis. 2010;42:320–30.
Papandreou D, Andreou E. Role of diet on non-alcoholic fatty liver disease: an updated narrative review. World J Hepatol. 2015;7:575.
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48.
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679–89.
EASL-EASD-EASO. Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.
Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–112.
Dyson J, Day C. Treatment of non-alcoholic fatty liver disease. Digestive Dis. 2014;32:597–604.
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–31.
Wong VW-S, Chan RS-M, Wong GL-H, Cheung BH-K, Chu WC-W, Yeung DK-W, et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2013;59:536–42.
He X-X, Wu X-L, Chen R-P, Chen C, Liu X-G, Wu B-J, et al. Effectiveness of omega-3 polyunsaturated fatty acids in non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. PLoS ONE. 2016;11:e0162368.
Yan J-H, Guan B-J, Gao H-Y, Peng X-E. Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Medicine. 2018;97:e12271
Parry SA, Hodson L. Influence of dietary macronutrients on liver fat accumulation and metabolism. J Investigative Med. 2017;65:1102–15.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e1000100.
Green S, Higgins J. Cochrane handbook for systematic reviews of interventions. Version, 2005.
ter Horst K, Serlie M. Fructose consumption, lipogenesis, and non-alcoholic fatty liver disease. Nutrients. 2017;9:981.
Chiu S, Sievenpiper J, De Souza R, Cozma A, Mirrahimi A, Carleton A, et al. Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr. 2014;68:416.
Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis–. Am J Clin Nutr. 2014;100:833–49.
Lu W, Li S, Li J, Wang J, Zhang R, Zhou Y, et al. Effects of omega-3 fatty acid in nonalcoholic fatty liver disease: a meta-analysis. Gastroenterol Res Pract. 2016;2016.
Yu L, Yuan M, Wang L. The effect of omega-3 unsaturated fatty acids on non-alcoholic fatty liver disease: a systematic review and meta-analysis of RCTs. Pak J Med Sci. 2017;33:1022.
Schrauwen P, van Marken Lichtenbelt W, Saris W, Westerterp KR. Changes in fat oxidation in response to a high-fat diet. Am J Clin Nutr. 1997;66:276–82.
Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol. 2009;51:433–45.
Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson imaging. 2011;34:729–49.
Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and mobile app for systematic reviews. Syst Rev. 2016;5:210.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin trials. 1986;7:177–88.
Luukkonen PK, S„devirta S, Zhou Y, Kayser B, Ali A, Ahonen L. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care. 2018;41:1732–9.
Cohen J. Statistical power analysis for the behavioral sciences. New York, US, Routledge; 2013.
Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial–. Am J Clin Nutr. 2012;95:1003–12.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ: British Medical Journal. 2003;327:557.
Higgins J, Green, S. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. http://www.cochrane-handbook.org.
Ras RT, Hiemstra H, Lin Y, Vermeer MA, Duchateau GS, Trautwein EA. Consumption of plant sterol-enriched foods and effects on plasma plant sterol concentrations–a meta-analysis of randomized controlled studies. Atherosclerosis. 2013;230:336–46.
Errazuriz I, Dube S, Slama M, Visentin R, Nayar S, O’connor H, et al. Randomized controlled trial of a MUFA or fiber-rich diet on hepatic fat in prediabetes. J Clin Endocrinol Metab. 2017;102:1765–74.
Haufe S, Engeli S, Kast P, Böhnke J, Utz W, Haas V, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011;53:1504–14.
Sterne JA, Egger M, Smith GD. Investigating and dealing with publication and other biases. Systematic Reviews in Health Care: Meta-Analysis in Context, Second Edition. 2001;323:101–5.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ: British Medical Journal. 1997;315:629–34.
van Herpen NA, Schrauwen-Hinderling VB, Schaart G, Mensink RP, Schrauwen P. Three weeks on a high-fat diet increases intrahepatic lipid accumulation and decreases metabolic flexibility in healthy overweight men. J Clin Endocrinol Metab. 2011;96:E691–5.
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ: British Medical Journal. 2011;343:d4002.
Bawden S, Stephenson M, Falcone Y, Lingaya M, Ciampi E, Hunter K, et al. Increased liver fat and glycogen stores after consumption of high versus low glycaemic index food: a randomized crossover study. Diabetes Obes Metab. 2017;19:70–7.
Bendsen NT, Chabanova E, Thomsen HS, Larsen TM, Newman JW, Stender S, et al. Effect of trans fatty acid intake on abdominal and liver fat deposition and blood lipids: a randomized trial in overweight postmenopausal women. Nutr Diabetes. 2011;1:e4.
Bozzetto L, Prinster A, Annuzzi G, Costagliola L, Mangione A, Vitelli A, et al. Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes Care. 2012;35:1429–35.
Kirk E, Reeds DN, Finck BN, Mayurranjan MS, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009;136:1552–60.
Marina A, Von Frankenberg AD, Suvag S, Callahan HS, Kratz M, Richards TL, et al. Effects of dietary fat and saturated fat content on liver fat and markers of oxidative stress in overweight/obese men and women under weight-stable conditions. Nutrients. 2014;6:4678–90.
Markova M, Pivovarova O, Hornemann S, Sucher S, Frahnow T, Wegner K, et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology. 2017;152:571–85.e8.
Martens EA, Gatta-Cherifi B, Gonnissen HK, Westerterp-Plantenga MS. The potential of a high protein-low carbohydrate diet to preserve intrahepatic triglyceride content in healthy humans. PloS ONE. 2014;9:e109617.
van Nielen M, Feskens EJ, Rietman A, Siebelink E, Mensink M. Partly replacing meat protein with soy protein alters insulin resistance and blood lipids in postmenopausal women with abdominal obesity, 2. J Nutr. 2014;144:1423–9.
Nosaka N, Kasai M, Nakamura M, Takahashi I, Itakura M, Takeuchi H, et al. Effects of dietary medium-chain triacylglycerols on serum lipoproteins and biochemical parameters in healthy men. Biosci Biotechnol Biochem. 2002;66:1713–8.
Ooi EM, Adams L, Zhu K, Lewis JR, Kerr DA, Meng X, et al. Consumption of a whey protein-enriched diet may prevent hepatic steatosis associated with weight gain in elderly women. Nutr Metab Cardiovascular Dis. 2015;25:388–95.
Rietman A, Schwarz J, Blokker BA, Siebelink E, Kok FJ, Afman LA, et al. Increasing protein intake modulates lipid metabolism in healthy young men and women consuming a high-fat hypercaloric diet–3. J Nutr. 2014;144:1174–80.
Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson H-E, Larsson A, et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes. 2014;63:2356–68.
Utzschneider KM, Bayer-Carter JL, Arbuckle MD, Tidwell JM, Richards TL, Craft S. Beneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjects. Br J Nutr. 2013;109:1096–104.
Westerbacka J, Lammi K, Häkkinen A-M, Rissanen A, Salminen I, Aro A, et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab. 2005;90:2804–9.
Gepner Y, Shelef I, Komy O, Cohen N, Schwarzfuchs D, Bril N, et al. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. J Hepatol. 2019. https://doi.org/10.1016/j.jhep.2019.04.013.
Schutte S, Esser D, Hoevenaars FPM, Hooiveld GJEJ, Priebe MG, Vonk RJ. et al. A 12-wk whole-grain wheat intervention protects against hepatic fat: the Graandioos study, a randomized trial in overweight subjects. Am J Clin Nutr. 2018;108:1264–74. https://doi.org/10.1093/ajcn/nqy204.
Chen Y, Feng R, Yang X, Dai J, Huang M, Ji X. et al. Yogurt improves insulin resistance and liver fat in obese women with nonalcoholic fatty liver disease and metabolic syndrome: a randomized controlled trial. Am J Clin Nutr. 2019;109:1611–9.
Marin-Alejandre BA, Abete I, Cantero I, Monreal JI, Elorz M, Herrero JI, et al. The metabolic and hepatic impact of two personalized dietary strategies in subjects with obesity and nonalcoholic fatty liver disease: the fatty liver in obesity (FLiO) randomized controlled trial. Nutrients. 2019;11. https://doi.org/10.3390/nu11102543.
Rosqvist F, Kullberg J, Ståhlman M, Cedernaes J, Heurling K, Johansson H-E, et al. Overeating saturated fat promotes fatty liver and ceramides compared with polyunsaturated fat: a randomized trial. J Clin Endocrinol Metab. 2019;104:6207–19.
Skytte MJ, Samkani A, Petersen AD, Thomsen MN, Astrup A, Chabanova E, et al. A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial. Diabetologia. 2019;62:2066–78.
Willmann C, Heni M, Linder K, Wagner R, Stefan N, Machann J. et al. Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study. Am J Clin Nutr. 2019;109:288–96. https://doi.org/10.1093/ajcn/nqy307.
Hodson L, Rosqvist F, Parry SA. The influence of dietary fatty acids on liver fat content and metabolism. Proc Nutr Soc. 2019:1–12. https://doi.org/10.1017/S0029665119000569.
Imamura F, Micha R, Wu JH, de Oliveira Otto MC, Otite FO, Abioye AI, et al. Effects of saturated fat, polyunsaturated fat, monounsaturated fat, and carbohydrate on glucose-insulin homeostasis: a systematic review and meta-analysis of randomised controlled feeding trials. PLoS Med. 2016;13:e1002087.
Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: pathophysiology, evidence, and practice. Hepatology. 2016;63:2032–43.
Hodson L, Fielding BA. Stearoyl-CoA desaturase: rogue or innocent bystander? Prog Lipid Res. 2013;52:15–42.
Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Prior JL, Weinberg ME, et al. Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat. J Clin Endocrinol Metab. 2015;100:2434–42.
We thank P.K. Luukkonen, S. Haufe, and M.R. Mensink for providing additional data for our analyses. We acknowledge the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). This research was in part financed by the Ministry of Economic Affairs and Climate Policy by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships and by Unilever R&D Vlaardingen.
Conflict of interest
MA, HP, and PZ were employees of Unilever R&D Vlaardingen at the time of this study. The other authors declare no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Winters-van Eekelen, E., Verkouter, I., Peters, H.P.F. et al. Effects of dietary macronutrients on liver fat content in adults: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr 75, 588–601 (2021). https://doi.org/10.1038/s41430-020-00778-1
This article is cited by
Relationship between liver fat content and lifestyle factors in adults with metabolic syndrome
Scientific Reports (2022)
Ketone bodies: from enemy to friend and guardian angel
BMC Medicine (2021)