The plasma lipidomic signature of nonalcoholic steatohepatitis

Specific alterations in hepatic lipid composition characterize the spectrum of nonalcoholic fatty liver disease (NAFLD), which extends from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). However, the plasma lipidome of NAFLD and whether NASH has a distinct plasma lipidomic signature are unknown. A comprehensive analysis of plasma lipids and eicosanoid metabolites quantified by mass spectrometry was performed in NAFL (n = 25) and NASH (n = 50) subjects and compared with lean normal controls (n = 50). The key findings include significantly increased total plasma monounsaturated fatty acids driven by palmitoleic (16:1 n7) and oleic (18:1 n9) acids content (P < 0.01 for both acids in both NAFL and NASH). The levels of palmitoleic acid, oleic acid, and palmitoleic acid to palmitic acid (16:0) ratio were significantly increased in NAFLD across multiple lipid classes. Linoleic acid (8:2n6) was decreased (P < 0.05), with a concomitant increase in γ‐linolenic (18:3n6) and dihomo γ‐linolenic (20:3n6) acids in both NAFL and NASH (P < 0.001 for most lipid classes). The docosahexanoic acid (22:6 n3) to docosapentenoic acid (22:5n3) ratio was significantly decreased within phosphatidylcholine (PC), and phosphatidylethanolamine (PE) pools, which was most marked in NASH subjects (P < 0.01 for PC and P < 0.001 for PE). The total plasmalogen levels were significantly decreased in NASH compared with controls (P < 0.05). A stepwise increase in lipoxygenase (LOX) metabolites 5(S)‐hydroxyeicosatetraenoic acid (5‐HETE), 8‐HETE, and 15‐HETE characterized progression from normal to NAFL to NASH. The level of 11‐HETE, a nonenzymatic oxidation product of arachidonic (20:4) acid, was significantly increased in NASH only. Conclusions: Although increased lipogenesis, desaturases, and LOX activities characterize NAFL and NASH, impaired peroxisomal polyunsaturated fatty acid (PUFA) metabolism and nonenzymatic oxidation is associated with progression to NASH. (HEPATOLOGY 2009;50:1827–1838.)

[1]  S. Watkins,et al.  Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism , 2008, Cell.

[2]  J. Schwimmer,et al.  Cardiovascular Risk Factors and the Metabolic Syndrome in Pediatric Nonalcoholic Fatty Liver Disease , 2008, Circulation.

[3]  G. Gores,et al.  The lysosomal‐mitochondrial axis in free fatty acid–induced hepatic lipotoxicity , 2008, Hepatology.

[4]  Michelle M Wiest,et al.  A lipidomic analysis of nonalcoholic fatty liver disease , 2007, Hepatology.

[5]  S. McCall,et al.  Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis , 2007, Hepatology.

[6]  M. Holmqvist,et al.  Long‐term follow‐up of patients with NAFLD and elevated liver enzymes , 2006, Hepatology.

[7]  B. Bistrian,et al.  Current Clinical Applications of Ω-6 and Ω-3 Fatty Acids. , 2006, Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition.

[8]  G. Gores,et al.  Free Fatty Acids Induce JNK-dependent Hepatocyte Lipoapoptosis* , 2006, Journal of Biological Chemistry.

[9]  G. Marchesini,et al.  Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease , 2005, Hepatology.

[10]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

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

[12]  G. Zoppini,et al.  Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. , 2004, Diabetes care.

[13]  G. Gores,et al.  Free fatty acids promote hepatic lipotoxicity by stimulating TNF‐α expression via a lysosomal pathway , 2004 .

[14]  G. Gores,et al.  O0040 FREE FATTY ACIDS PROMOTE HEPATIC LIPOTOXICITY BY STIMULATING TNF‐ALPHA EXPRESSION VIA A LYSOSOMAL PATHWAY , 2004, Journal of Pediatric Gastroenterology and Nutrition.

[15]  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.

[16]  M. Miyazaki,et al.  Regulation of stearoyl-CoA desaturases and role in metabolism. , 2004, Progress in lipid research.

[17]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference , 2003, Hepatology.

[18]  J. Bruce German,et al.  Lipid metabolome-wide effects of the PPARγ agonist rosiglitazones⃞s The online version of this article (available at http://www.jlr.org) contains an additional 4 tables. Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200169-JLR200 , 2002, Journal of Lipid Research.

[19]  Joseph L Goldstein,et al.  SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. , 2002, The Journal of clinical investigation.

[20]  R. Karim,et al.  NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome , 2002, Hepatology.

[21]  A. Sanyal,et al.  The Clinicopathologic Spectrum and Management of Nonalcoholic Fatty Liver Disease , 2002, Advances in anatomic pathology.

[22]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[23]  S. Ferdinandusse,et al.  Identification of the peroxisomal beta-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid. , 2001, Journal of lipid research.

[24]  J. Warrington,et al.  Identification of a Mammalian Long Chain Fatty Acyl Elongase Regulated by Sterol Regulatory Element-binding Proteins* , 2001, The Journal of Biological Chemistry.

[25]  J. Ntambi,et al.  Cloning and characterization of the human stearoyl-CoA desaturase gene promoter: transcriptional activation by sterol regulatory element binding protein and repression by polyunsaturated fatty acids and cholesterol. , 2001, Biochemical and biophysical research communications.

[26]  J. Clore,et al.  Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. , 2001, Gastroenterology.

[27]  J. German,et al.  Unique phospholipid metabolism in mouse heart in response to dietary docosahexaenoic or α-linolenic acids , 2001, Lipids.

[28]  J. Ruiz,et al.  Quantification in the subnanomolar range of phospholipids and neutral lipids by monodimensional thin-layer chromatography and image analysis. , 1997, Journal of lipid research.

[29]  B. S. Mohammed,et al.  Regulation of the Biosynthesis of 4,7,10,13,16,19-Docosahexaenoic Acid* , 1996, The Journal of Biological Chemistry.

[30]  E. Stahl.  Thin Layer Chromatography: A Laboratory Handbook , 1969 .

[31]  R. Holman,et al.  The ratio of trienoic: tetraenoic acids in tissue lipids as a measure of essential fatty acid requirement. , 1960, The Journal of nutrition.

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

[33]  N. Unwin,et al.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Detection, Evaluation, and Treatment of High Blood Cholesterol Education Program (NCEP) Expert Panel on Executive Summary of the Third Report of the National , 2009 .

[34]  B. Bistrian,et al.  Current clinical applications of omega-6 and omega-3 fatty acids. , 2006, Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition.

[35]  Y. Sakakihara,et al.  Alterations of fatty acid metabolism and membrane fluidity in peroxisome-defective mutant ZP102 cells , 2004, Lipids.

[36]  J Bruce German,et al.  Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. , 2002, Journal of lipid research.

[37]  Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. , 2002, Circulation.

[38]  J. Ludwig,et al.  Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. , 1980, Mayo Clinic proceedings.