Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

[1]  J. McDonald,et al.  Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis. , 2015, Cell metabolism.

[2]  M. Anitha,et al.  An Intestinal Farnesoid X Receptor–Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice , 2016, Diabetes.

[3]  Hannele Yki-Järvinen,et al.  Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance , 2015, Nutrients.

[4]  C. Knauf,et al.  Comment on: Cani et al. (2007) Metabolic Endotoxemia Initiates Obesity and Insulin Resistance: Diabetes , 2007 .

[5]  L. Carlsson,et al.  Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver , 2017, Journal of internal medicine.

[6]  F. Hu,et al.  Total and subtypes of dietary fat intake and risk of type 2 diabetes mellitus in the Prevención con Dieta Mediterránea (PREDIMED) study. , 2017, The American journal of clinical nutrition.

[7]  I. Nookaew,et al.  Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods , 2013, Nucleic acids research.

[8]  L. Groop,et al.  Demonstration of a novel feedback mechanism between FFA oxidation from intracellular and intravascular sources. , 1991, The American journal of physiology.

[9]  J. Levine,et al.  Weekly Changes in Basal Metabolic Rate with Eight Weeks of Overfeeding , 2006, Obesity.

[10]  Pelin Yilmaz,et al.  The SILVA ribosomal RNA gene database project: improved data processing and web-based tools , 2012, Nucleic Acids Res..

[11]  W. Dunn,et al.  Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man , 2015, The Journal of clinical endocrinology and metabolism.

[12]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.

[13]  B. Fielding,et al.  Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. , 2008, Progress in lipid research.

[14]  S. Summers,et al.  Could Ceramides Become the New Cholesterol? , 2018, Cell metabolism.

[15]  Y. Jang,et al.  Standards of Medical Care in Diabetes-2010 by the American Diabetes Association: Prevention and Management of Cardiovascular Disease , 2010 .

[16]  D. Clegg,et al.  Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. , 2011, The Journal of clinical investigation.

[17]  Janne Nikkilä,et al.  Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. , 2010, Journal of microbiological methods.

[18]  J. Borén,et al.  Hepatic lipogenesis and a marker of hepatic lipid oxidation, predict postprandial responses of triglyceride‐rich lipoproteins , 2014, Obesity.

[19]  A. Häkkinen,et al.  Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. , 2003, Diabetes.

[20]  H. Yki-Järvinen Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. , 2014, The lancet. Diabetes & endocrinology.

[21]  Fredrik Karpe,et al.  Selective partitioning of dietary fatty acids into the VLDL TG pool in the early postprandial period Published, JLR Papers in Press, August 16, 2003. DOI 10.1194/jlr.M300167-JLR200 , 2003, Journal of Lipid Research.

[22]  J. Browning,et al.  Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. , 2014, Gastroenterology.

[23]  J. Borén,et al.  Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women , 2015, Journal of the American Heart Association.

[24]  M. Beylot,et al.  Measuring lipogenesis and cholesterol synthesis in humans with deuterated water: use of simple gas chromatographic/mass spectrometric techniques. , 1997, Journal of mass spectrometry : JMS.

[25]  Sarah L. Westcott,et al.  Development of a Dual-Index Sequencing Strategy and Curation Pipeline for Analyzing Amplicon Sequence Data on the MiSeq Illumina Sequencing Platform , 2013, Applied and Environmental Microbiology.

[26]  Michael Miller,et al.  Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association , 2017, Circulation.

[27]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[28]  N. Lundbom,et al.  Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. , 2012, The American journal of clinical nutrition.

[29]  S. Watkins,et al.  GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-inflammatory and Insulin-Sensitizing Effects , 2010, Cell.

[30]  M. Birnbaum,et al.  Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. , 2007, Cell metabolism.

[31]  J. Ferrières,et al.  Metabolic Endotoxemia Initiates Obesity and Insulin Resistance , 2007, Diabetes.

[32]  S. Summers,et al.  A ceramide-centric view of insulin resistance. , 2012, Cell metabolism.

[33]  M. McDowell US Department of Health and Human Services—US Department of Agriculture survey integration activities , 2003 .

[34]  B. M. Rasmussen,et al.  Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU study , 2001, Diabetologia.

[35]  Robert C. Edgar,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2001 .

[36]  Matthias Blüher,et al.  Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. , 2014, Cell metabolism.

[37]  G. Musso,et al.  Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis , 2003, Hepatology.

[38]  M. Orešič,et al.  Ceramides Dissociate Steatosis and Insulin Resistance in the Human Liver in Non-Alcoholic Fatty Liver Disease Short title : Ceramides in Human Non-Alcoholic Fatty Liver Disease , 2016 .

[39]  A. Häkkinen,et al.  Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity , 2007, Diabetes.

[40]  J. López-Miranda,et al.  A Mediterranean and a high-carbohydrate diet improve glucose metabolism in healthy young persons , 2001, Diabetologia.

[41]  J. Stoker,et al.  The Department of Health and Human Services. , 1999, Home healthcare nurse.

[42]  S. O’Rahilly,et al.  Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. , 2009, The Journal of clinical investigation.

[43]  S. Neubauer,et al.  Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men. , 2015, The Journal of clinical endocrinology and metabolism.

[44]  B. Fielding,et al.  Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity , 2002, Diabetologia.

[45]  R. Kreis,et al.  Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men. , 2010, Diabetes & metabolism.

[46]  B. Morio,et al.  Overfeeding increases postprandial endotoxemia in men: Inflammatory outcome may depend on LPS transporters LBP and sCD14. , 2014, Molecular nutrition & food research.

[47]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[48]  D. Mozaffarian,et al.  Changes in diet and lifestyle and long-term weight gain in women and men. , 2011, The New England journal of medicine.

[49]  S. Summers,et al.  CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. , 2014, Cell metabolism.

[50]  S. Neubauer,et al.  Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults , 2016, Diabetes.

[51]  M. Blüher,et al.  Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance , 2015, Diabetes.

[52]  S. Caprio,et al.  Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. , 2015, The Journal of clinical endocrinology and metabolism.

[53]  L. Groop,et al.  Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD. , 2017, Journal of hepatology.

[54]  Patrice D. Cani,et al.  Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling , 2015, Cell metabolism.

[55]  A. Larsson,et al.  Overfeeding Polyunsaturated and Saturated Fat Causes Distinct Effects on Liver and Visceral Fat Accumulation in Humans , 2014, Diabetes.

[56]  M. Wang,et al.  Omega-3 polyunsaturated fatty acids ameliorate ethanol-induced adipose hyperlipolysis: A mechanism for hepatoprotective effect against alcoholic liver disease. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[57]  M. Uusitupa,et al.  Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. , 2012, The American journal of clinical nutrition.