Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis.

BACKGROUND Biochemical evidence has linked the coordinate control of fatty acid (FA) synthesis with the activity of stearoyl-CoA desaturase-1 (SCD1). The ratio of 16:1n-7 to 16:0 [SCD1₁₆] in plasma triacylglycerol FA has been used as an index to reflect liver SCD1₁₆ activity and has been proposed as a biomarker of FA synthesis, although this use has not been validated by comparison with isotopically measured de novo lipogenesis (DNL(Meas)). OBJECTIVE We investigated plasma lipid 16:1n-7 and FA indexes of elongation and desaturation in relation to lipogenesis. DESIGN In this cross-sectional investigation of metabolism, 24 overweight adults, who were likely to have elevated DNL, consumed D2O for 10 d and had liver fat (LF) measured by magnetic resonance spectroscopy. Very-low-density lipoprotein (VLDL)-triacylglycerols and plasma free FA [nonesterified fatty acids (NEFAs)] were analyzed by using gas chromatography for the FA composition (molar percentage) and gas chromatography-mass spectrometry and gas chromatography-combustion isotope ratio mass spectrometry for deuterium enrichment. RESULTS In all subjects, VLDL-triacylglycerol 16:1n-7 was significantly (P < 0.01) related to DNL(Meas) (r = 0.56), liver fat (r = 0.53), and adipose insulin resistance (r = 0.56); similar positive relations were shown with the SCD1₁₆ index, and the pattern in NEFAs echoed that of VLDL-triacylglycerols. Compared with subjects with low LF (3.1 ± 2.7%; n = 11), subjects with high LF (18.4 ± 3.6%; n = 13) exhibited a 45% higher VLDL-triacylglycerol 16:1n-7 molar percentage (P < 0.01), 16% of subjects had lower 18:2n-6 (P = 0.01), and 27% of subjects had higher DNL as assessed by using a published DNL index (ratio of 16:0 to 18:2n-6; P = 0.03), which was isotopically confirmed by DNL(Meas) (increased 2.5-fold; P < 0.01). Compared with 16:0 in the diet, the low amount of dietary 16:1n-7 in VLDL-triacylglycerols corresponded to a stronger signal of elevated DNL. CONCLUSION The current data provide support for the use of the VLDL-triacylglycerol 16:1n-7 molar percentage as a biomarker for elevated liver fat when isotope use is not feasible; however, larger-scale confirmatory studies are needed.

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

[2]  M. Jensen,et al.  Systemic Free Fatty Acid Disposal Into Very Low-Density Lipoprotein Triglycerides , 2013, Diabetes.

[3]  F. Karpe,et al.  Is there something special about palmitoleate? , 2013, Current opinion in clinical nutrition and metabolic care.

[4]  F. Schick,et al.  High hepatic SCD1 activity is associated with low liver fat content in healthy subjects under a lipogenic diet. , 2012, The Journal of clinical endocrinology and metabolism.

[5]  H. Guillou,et al.  The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. , 2012, The Journal of clinical investigation.

[6]  J. Hardies,et al.  Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease , 2012, Hepatology.

[7]  B. Vessby,et al.  Plasma lipid fatty acid composition, desaturase activities and insulin sensitivity in Amerindian women. , 2012, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[8]  Scott E. Crouter,et al.  Validity of the Actical for estimating free-living physical activity , 2011, European Journal of Applied Physiology.

[9]  S. Klein,et al.  Insulin sensitivity is not associated with palmitoleate availability in obese humans , 2011, Journal of Lipid Research.

[10]  E. Schleicher,et al.  Relationships between hepatic stearoyl-CoA desaturase-1 activity and mRNA expression with liver fat content in humans. , 2011, American journal of physiology. Endocrinology and metabolism.

[11]  M. Hellerstein,et al.  A dual sugar challenge test for lipogenic sensitivity to dietary fructose. , 2011, The Journal of clinical endocrinology and metabolism.

[12]  D. Mozaffarian,et al.  Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. , 2010, The American journal of clinical nutrition.

[13]  W. Kraemer,et al.  Limited Effect of Dietary Saturated Fat on Plasma Saturated Fat in the Context of a Low Carbohydrate Diet , 2010, Lipids.

[14]  M. Neville,et al.  De Novo Lipogenesis and Stearoyl-CoA Desaturase Are Coordinately Regulated in the Human Adipocyte and Protect against Palmitate-induced Cell Injury* , 2009, The Journal of Biological Chemistry.

[15]  E. Schleicher,et al.  Hepatic lipid composition and stearoyl-coenzyme A desaturase 1 mRNA expression can be estimated from plasma VLDL fatty acid ratios. , 2009, Clinical chemistry.

[16]  L. J. Hardies,et al.  Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis , 2009, Hepatology.

[17]  U. de Faire,et al.  Associations between estimated fatty acid desaturase activities in serum lipids and adipose tissue in humans: links to obesity and insulin resistance , 2009, Lipids in Health and Disease.

[18]  Maaike H. Oosterveer,et al.  High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice , 2009, PloS one.

[19]  E. Ryan,et al.  Synthesis of specific fatty acids contributes to VLDL-triacylglycerol composition in humans with and without type 2 diabetes , 2009, Diabetologia.

[20]  F. Schick,et al.  Individual Stearoyl-CoA Desaturase 1 Expression Modulates Endoplasmic Reticulum Stress and Inflammation in Human Myotubes and Is Associated With Skeletal Muscle Lipid Storage and Insulin Sensitivity In Vivo , 2009, Diabetes.

[21]  M. Neville,et al.  Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans , 2009, Diabetologia.

[22]  A. Feldstein,et al.  Hepatic Lipid Partitioning and Liver Damage in Nonalcoholic Fatty Liver Disease , 2009, Journal of Biological Chemistry.

[23]  M. Orešič,et al.  Hepatic Stearoyl-CoA Desaturase (SCD)-1 Activity and Diacylglycerol but Not Ceramide Concentrations Are Increased in the Nonalcoholic Human Fatty Liver , 2009, Diabetes.

[24]  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.

[25]  J. Daubert,et al.  Plasma palmitoleic acid, a product of stearoyl-coA desaturase activity, is an independent marker of triglyceridemia and abdominal adiposity. , 2008, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[26]  F. Karpe,et al.  Parallel activation of de novo lipogenesis and stearoyl-CoA desaturase activity after 3 d of high-carbohydrate feeding. , 2008, The American journal of clinical nutrition.

[27]  M. Sherman,et al.  Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study. , 2008, Journal of hepatology.

[28]  A. Hamsten,et al.  Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance , 2008, Diabetologia.

[29]  M. Hellerstein,et al.  Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans Published, JLR Papers in Press, August 23, 2006. , 2006, Journal of Lipid Research.

[30]  E. Parks,et al.  Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. , 2006, The Journal of clinical endocrinology and metabolism.

[31]  E. Murphy,et al.  Stable isotope methods for the in vivo measurement of lipogenesis and triglyceride metabolism. , 2006, Journal of animal science.

[32]  J. Drai,et al.  Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. , 2005, The American journal of clinical nutrition.

[33]  R. Krauss,et al.  Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement , 2005, Current opinion in cardiology.

[34]  E. Parks,et al.  Increased dietary substrate delivery alters hepatic fatty acid recycling in healthy men. , 2005, Diabetes.

[35]  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.

[36]  S. Grundy,et al.  Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. , 2005, American journal of physiology. Endocrinology and metabolism.

[37]  Jonathan C. Cohen,et al.  Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity , 2004, Hepatology.

[38]  R. Rodrigo,et al.  Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. , 2004, Clinical science.

[39]  M. Hellerstein,et al.  Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O. , 2004, American journal of physiology. Endocrinology and metabolism.

[40]  D. Jump,et al.  Fatty Acid Regulation of Gene Transcription , 2004, Critical reviews in clinical laboratory sciences.

[41]  M. Beylot,et al.  Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. , 2003, Diabetes & metabolism.

[42]  S. Turner,et al.  Measurement of TG synthesis and turnover in vivo by 2H2O incorporation into the glycerol moiety and application of MIDA. , 2003, American journal of physiology. Endocrinology and metabolism.

[43]  Robert V Farese,et al.  Triglyceride accumulation protects against fatty acid-induced lipotoxicity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Brownlie,et al.  Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200189-JLR200 , 2002, Journal of Lipid Research.

[45]  I. T. de Almeida,et al.  Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. , 2002, Clinical nutrition.

[46]  J. Martínez,et al.  Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men. , 2001, The American journal of clinical nutrition.

[47]  M. Hellerstein,et al.  Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. , 2000, Journal of lipid research.

[48]  M. Hellerstein De novo lipogenesis in humans: metabolic and regulatory aspects , 1999, European Journal of Clinical Nutrition.

[49]  R. Wolfe,et al.  Hepatic secretion of VLDL fatty acids during stimulated lipogenesis in men. , 1998, Journal of lipid research.

[50]  J. Brenna Use of stable isotopes to study fatty acid and lipoprotein metabolism in man. , 1997, Prostaglandins, leukotrienes, and essential fatty acids.

[51]  J Hirsch,et al.  Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. , 1996, The Journal of clinical investigation.

[52]  E. Emken Metabolism of dietary stearic acid relative to other fatty acids in human subjects. , 1994, The American journal of clinical nutrition.

[53]  E. Ryan,et al.  Diet fat composition alters membrane phospholipid composition, insulin binding, and glucose metabolism in adipocytes from control and diabetic animals. , 1990, The Journal of biological chemistry.

[54]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[55]  P. Emmett,et al.  The effect of a low-cholesterol, high-polyunsaturate diet on serum lipid levels, apolipoprotein B levels and triglyceride fatty acid composition. , 1977, Atherosclerosis.

[56]  Zhijin Wu,et al.  Adipose tissue palmitoleic acid and obesity in humans: does it behave as a lipokine? , 2011, The American journal of clinical nutrition.

[57]  J. Schwarz,et al.  Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. , 2003, The American journal of clinical nutrition.

[58]  A. Stunkard,et al.  Assessment of dietary and genetic factors influencing serum and adipose fatty acid composition in obese female identical twins , 2002, Lipids.

[59]  L. Sjöström Fatty acid synthesis de novo in adipose tissue from obese subjects on a hypercaloric high-carbohydrate diet. , 1973, Scandinavian journal of clinical and laboratory investigation.