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Determinants of ectopic liver fat in metabolic disease

European Journal of Clinical Nutrition volume 73, pages 209–214 (2019)Cite this article

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Abstract

Common obesity-associated hepatic steatosis (nonalcoholic fatty liver disease (NAFLD)) and insulin resistance are mainly caused by dysfunctional adipose tissue. This adipose tissue dysfunction leads to increased delivery of NEFA and glycerol to the liver that (i) drives hepatic gluconeogenesis and (ii) facilitates the accumulation of lipids and insulin signaling inhibiting lipid intermediates. Dysfunctional adipose tissue can be caused by impaired lipid storage (overflow hypothesis, characterized by large visceral adipocytes) or increased lipolysis (due to impaired postprandial suppression of lipolysis in inflamed, insulin-resistant adipocytes). In line with the adipose tissue expandability hypothesis the amount and distribution of adipose tissue correlate with its dysfunction and thus with liver fat. This relationship is however modified by endocrine effects on lipid storage and lipolysis as well as dietary effects on hepatic lipogenesis and lipid oxidation. The association between body composition characteristics like visceral obesity or fat cell size and ectopic liver fat is modified by these influences. Phenotyping obesity according to metabolic risk should integrate body composition characteristics, endocrine parameters and information on diet.

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References

  1. Kneeman JM, Misdraji J, Corey KE. Secondary causes of nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2012;5:199–207.

    Article  Google Scholar 

  2. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA. 2009;106:15430–5.

    Article  CAS  Google Scholar 

  3. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shurman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603–8.

    Article  CAS  Google Scholar 

  4. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54:2506–14.

    Article  CAS  Google Scholar 

  5. Bosy-Westphal A, Kossel E, Goele K, Blöcker T, Lagerpusch M, Later W, et al. Association of pericardial fat with liver fat and insulin sensitivity after diet-induced weight loss in overweight women. Obesity (Silver Spring). 2010;18:2111–7.

    Article  CAS  Google Scholar 

  6. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109:1345–50.

    Article  CAS  Google Scholar 

  7. Parry SA, Hodson L. Influence of dietary macronutrients on liver fat accumulation and metabolism. J Investig Meg. 2017;65:1102–15.

    Article  Google Scholar 

  8. Ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, et al. Hepatic diacylglycerol-associated protein kinase Cε translocation links hepatic steatosis to hepatic insulin resistance in humans. Cell Rep. 2017;19:1997–2004.

    Article  Google Scholar 

  9. Magkos F, Su X, Bradley D, Fabbrini E, Conte C, Eagon JC, et al. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology. 2012;142:1444–6.e2.

    Article  CAS  Google Scholar 

  10. Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 2017;13:572–87.

    Article  CAS  Google Scholar 

  11. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.

    Article  CAS  Google Scholar 

  12. Coppack SW, Fisher RM, Gibbons GF, Humphreys SM, McDonough MJ, Potts JC, et al. Postprandial substrate deposition in human forearm and adipose tissues in vivo. Clin Sci. 1990;79:339–48.

    Article  CAS  Google Scholar 

  13. Frayn KN, Coppack SW, Fielding BA, Humphreys SM. Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization. Adv Enzym Regul. 1995;35:163–78.

    Article  CAS  Google Scholar 

  14. Christodoulides C, Vidal-Puig A. PPARs and adipocyte function. Mol Cell Endocrinol. 2010;318:61–8.

    Article  CAS  Google Scholar 

  15. Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156:20–44.

    Article  CAS  Google Scholar 

  16. Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233:104–12.

    Article  CAS  Google Scholar 

  17. Nielsen S, Guo ZK, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest. 2004;95:1846–53.

    Google Scholar 

  18. Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res. 2005;2:105–12.

    Article  Google Scholar 

  19. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007;116:39–48.

    Article  Google Scholar 

  20. Bosy-Westphal A, Braun W, Geisler C, Norman K, Müller MJ. Body composition and cardiometabolic health: the need for novel concepts. Eur J Clin Nutr. 2018;72:638–44.

    Article  Google Scholar 

  21. Alligier M, Gabert L, Meugnier E, Lambert-Porcheron S, Chanseaume E, Pilleul F, et al. Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. J Clin Endocrinol Metab. 2013;98:802–10.

    Article  CAS  Google Scholar 

  22. Johannsen DL, Tchoukalova Y, Tam CS, Covington JD, Xie W, Schwarz JM, et al. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the “adipose tissue expandability” hypothesis. Diabetes Care. 2014;37:2789–97.

    Article  CAS  Google Scholar 

  23. Mittendorfer B, Magkos F, Fabbrini E, Mohammed BS, Klein S. Relationship between body fat mass and free fatty acid kinetics in men and women. Obesity (Silver Spring). 2009;17:1872–7.

    Article  CAS  Google Scholar 

  24. Hübers M, Geisler C, Bosy-Westphal A, Braun W, Pourhassan M, Sørensen TIA et al. Association between fat mass, adipose tissue, fat fraction per adipose tissue, and metabolic risks: a cross-sectional study in normal, overweight, and obese adults. Eur J Clin Nutr. 2018. https://doi.org/10.1038/s41430-018-0150-x.

    Article  Google Scholar 

  25. Moller L, Stodkilde-Jorgensen H, Jensen FT, Jorgensen JO. Fasting in healthy subjects is associated with intrahepatic accumulation of lipids as assessed by 1H-magnetic resonance spectroscopy. Clin Sci (Lond). 2008;114:547–52.

    Article  CAS  Google Scholar 

  26. Browning JD, Baxter J, Satapati S, Burgess SC. The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. J Lipid Res. 2012;53:577–86.

    Article  CAS  Google Scholar 

  27. Egger A, Kreis R, Allemann S, Stettler C, Diem P, Buehler T, et al. The effect of aerobic exercise on intrahepatocellular and intramyocellular lipids in healthy subjects. PLoS One. 2013;8:e70865.

    Article  CAS  Google Scholar 

  28. Golabi P, Locklear CT, Austin P, Afdhal S, Byrns M, Gerber L, et al. Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: systematic review. World J Gastroenterol. 2016;22:6318–27.

    Article  Google Scholar 

  29. Gan SK, Watts GF. Is adipose tissue lipolysis always an adaptive response to starvation?: implications for non-alcoholic fatty liver disease. Clin Sci (Lond). 2008;114:543–5.

    Article  CAS  Google Scholar 

  30. Afolabi PR, Scorletti E, Smith DE, Almehmadi AA, Calder PC, Byrne CD. The characterisation of hepatic mitochondrial function in patients with non-alcoholic fatty liver disease (NAFLD) using the 13C-ketoisocaproate breath test. J Breath Res. 2018;12:046002.

    Article  CAS  Google Scholar 

  31. Liu G, Zheng X, Guan L, Jiang Z, Lin H, Jiang Q, et al. Free triiodothyronine levels are positively associated with non-alcoholic fatty liver disease in euthyroid middle-aged subjects. Endocr Res. 2015;40:188–93.

    Article  CAS  Google Scholar 

  32. van den Berg EH, van Tienhoven-Wind LJ, Amini M, Schreuder TC, Faber KN, Blokzijl H, et al. Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study. Metabolism. 2017;67:62–71.

    Article  Google Scholar 

  33. Longhi S, Radetti G. Thyroid function and obesity. J Clin Res Pediatr Endocrinol. 2013;5 Suppl 1:40–44.

    PubMed  PubMed Central  Google Scholar 

  34. Diamant S, Gorin E, Shafrir E. Enzyme activities related to fatty-acid synthesis in liver and adipose tissue of rats treated with triiodothyronine. Eur J Biochem. 1972;26:553–9.

    Article  CAS  Google Scholar 

  35. Haluzik M, Nedvidkova J, Bartak V, Dostalova I, Vlcek P, Racek P, et al. Effects of hypo- and hyperthyroidism on noradrenergic activity and glycerol concentrations in human subcutaneous abdominal adipose tissue assessed with microdialysis. J Clin Endocrinol Metab. 2003;88:5605–8.

    Article  CAS  Google Scholar 

  36. Lange T, Budde K, Homuth G, Kastenmüller G, Artati A, Krumsiek J, et al. Comprehensive metabolic profiling reveals a lipid-rich fingerprint of free thyroxine far beyond classic parameters. J Clin Endocrinol Metab. 2018;103:2050–60.

    Article  Google Scholar 

  37. Klieverik LP, Coomans CP, Endert E, Sauerwein HP, Havekar LM, Vostol PJ, et al. Thyroid hormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivo. Endocrinology. 2009;150:5639–48.

    Article  CAS  Google Scholar 

  38. Oppenheimer JH, Schwartz HL, Lane JT, Thompson MP. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat. J Clin Invest. 1991;87:125–32.

    Article  CAS  Google Scholar 

  39. Cioffi F, Lanni A, Goglia F. Thyroid hormones, mitochondrial bioenergetics and lipid handling. Curr Opin Endocrinol Diabetes Obes. 2010;17:402–7.

    Article  CAS  Google Scholar 

  40. Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018;14:259–69.

    Article  CAS  Google Scholar 

  41. Einer C, Hohenester S, Wimmer R, Wottke L, Artmann R, Schulz S. et al. Mitochondrial adaptation in steatotic mice. Mitochondrion. 2018;40:1–12.

    Article  CAS  Google Scholar 

  42. Simõnes ICM, Fontes A, Pinton P, Zischka H, Wieckowsk MR. Mitochondria in non-alcoholic fatty liver disease. Int J Biochem Cell Biol. 2018;95:93–99.

    Article  Google Scholar 

  43. Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul). 2018;33:33–43.

    Article  CAS  Google Scholar 

  44. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53:372–84.

    Article  Google Scholar 

  45. Lindeboom L, Nabuurs CI, Hesselink MK, Wildberger JE, Schrauwen P, Schrauwen-Hinderling VB. Proton magnetic resonance spectroscopy reveals increased hepatic lipid content after a single high-fat meal with no additional modulation by added protein. Am J Clin Nutr. 2015;101:65–71.

    Article  CAS  Google Scholar 

  46. Ravikumar B, Carey PE, Snaar JE, Deelchand DK, Cook DB, Neely RD, et al. Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes. Am J Physiol Endocrinol Metab. 2005;288:E789–97.

    Article  CAS  Google Scholar 

  47. Hernández EÁ, Kahl S, Seelig A, Begovatz P, Irmler M, Kupriyanova Y. et al. Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance. J Clin Invest. 2017;127:695–708.

    Article  Google Scholar 

  48. Kratz M, Marcovina S, Nelson JE, Yeh MM, Kowdley KV, Callahan HS, et al. Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not β-cell function in humans. Am J Clin Nutr. 2014;99:1385–96.

    Article  CAS  Google Scholar 

  49. 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.

    Article  Google Scholar 

  50. Bozzetto L, Costabile G, Luongo D, Naviglio D, Cicala V, Piantadosi C, et al. Reduction in liver fat by dietary MUFA in type 2 diabetes is helped by enhanced hepatic fat oxidation. Diabetologia. 2016;59:2697–701.

    Article  CAS  Google Scholar 

  51. 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.

    Article  CAS  Google Scholar 

  52. Della Pepa G, Vetrani C, Lombardi G, Bozzetto L, Annuzzi G, Rivellese AA. Isocaloric dietary changes and non-alcoholic fatty liver disease in high cardiometabolic risk individuals. Nutrients. 2017;9:pii: E1065

    Article  Google Scholar 

  53. Westerbacka J, Lammi K, Häkkinen AM, 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.

    Article  CAS  Google Scholar 

  54. Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson HE, 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.

    Article  Google Scholar 

  55. El-Badry AM, Graf R, Clavien PA. Omega 3 - Omega 6: what is right for the liver? J Hepatol. 2007;47:718–25.

    Article  CAS  Google Scholar 

  56. Timlin MT, Parks EJ. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men. Am J Clin Nutr. 2005;81:35–42.

    Article  CAS  Google Scholar 

  57. Flannery C, Dufour S, Rabol R, Shulman GI, Petersen KF. Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes. 2012;61:2711–2717.

    Article  CAS  Google Scholar 

  58. Ma W, Wu JH, Wang Q, Lemaitre RN, Mukamal KJ, Djousse L, et al. Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. Am J Clin Nutr. 2015;101:153–63.

    Article  CAS  Google Scholar 

  59. Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab.2008;7:95–6.

    Article  CAS  Google Scholar 

  60. Saponaro C, Gaggini M, Carli F, Gastaldelli A. The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients. 2015;7:9453–74.

    Article  CAS  Google Scholar 

  61. Lagerpusch M, Enderle J, Eggeling B, Braun W, Johannsen M, Pape D, et al. Carbohydrate quality and quantity affect glucose and lipid metabolism during weight regain in healthy men. J Nutr. 2013;143:1593–601.

    Article  CAS  Google Scholar 

  62. Nseir W, Nassar F, Assy N. Soft drinks consumption and nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:2579–88.

    Article  CAS  Google Scholar 

  63. Ma J, Fox CS, Jacques PF, Speliotes EK, Hoffmann U, Smith CE, et al. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts. J Hepatol. 2015;63:462–9.

    Article  CAS  Google Scholar 

  64. Tajima R, Kimura T, Enomoto A, Yanoshita K, Saito A, Kobayashi S, et al. Association between rice, bread, and noodle intake and the prevalence of non-alcoholic fatty liver disease in Japanese middle-aged men and women. Clin Nutr. 2017;36:1601–8.

    Article  Google Scholar 

  65. 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.

    Article  CAS  Google Scholar 

  66. Bravo S, Lowndes J, Sinnett S, Yu Z, Rippe J. Consumption of sucrose and high-fructose corn syrup does not increase liver fat or ectopic fat deposition in muscles. Appl Physiol Nutr Metab. 2013;38:681–8.

    Article  CAS  Google Scholar 

  67. Jin R, Welsh JA, Le NA, Holzberg J, Sharma P, Martin DR, et al. Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD. Nutrients. 2014;6:3187–201.

    Article  Google Scholar 

  68. Johnston RD, Stephenson MC, Crossland H, Cordon SM, Palcidi E, Cox EF, et al. No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men. Gastroenterology. 2013;145:1016–25.

    Article  CAS  Google Scholar 

  69. Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134:424–31.

    Article  CAS  Google Scholar 

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  1. Institute for Human Nutrition and Food Science, Christian-Albrechts-University Kiel, Kiel, Germany

    Anja Bosy-Westphal, Wiebke Braun, Viktoria Albrecht & Manfred J. Müller

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Bosy-Westphal, A., Braun, W., Albrecht, V. et al. Determinants of ectopic liver fat in metabolic disease. Eur J Clin Nutr 73, 209–214 (2019). https://doi.org/10.1038/s41430-018-0323-7

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