Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors

BMC Infectious Diseases

Volumn 13, Issue 1, 2013, Pages

  Cassol, Edana ^a,b   Misra, Vikas ^a   Holman, Alexander ^a   Kamat, Anupa ^a,b   Morgello, Susan ^c   Gabuzda, Dana ^a,b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c MOUNT SINAI MEDICAL CENTER   (United States)

Author keywords

Antiretroviral therapy; Dyslipidemia; HCV; Hepatic dysfunction; HIV; Inflammation; Metabolomics; Protease inhibitors

Indexed keywords

ACYLCARNITINE; ALPHA INTERFERON; AMPRENAVIR; ATAZANAVIR PLUS RITONAVIR; BILE ACID; BIOLOGICAL MARKER; CELL NUCLEUS RECEPTOR; FOSAMPRENAVIR PLUS RITONAVIR; GLYCEROPHOSPHOLIPID; ICOSANOID; INDINAVIR PLUS RITONAVIR; INTERLEUKIN 6; LIPID; LIPIDOME; LIPOPOLYSACCHARIDE; LOPINAVIR PLUS RITONAVIR; NELFINAVIR; POLYUNSATURATED FATTY ACID; PROTEIN APRI; PROTEIN FIB 4; PROTEIN YLK 40; PROTEINASE INHIBITOR; RITONAVIR; RITONAVIR PLUS SAQUINAVIR; STEROID; UNCLASSIFIED DRUG;

ADULT; ARTICLE; CD4 LYMPHOCYTE COUNT; CLINICAL ARTICLE; CONTROLLED STUDY; DISEASE MARKER; FEMALE; GAS CHROMATOGRAPHY; HEPATITIS C; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFLAMMATION; LIPID BLOOD LEVEL; LIQUID CHROMATOGRAPHY; LIVER FIBROSIS; LIVER FUNCTION; MALE; MASS SPECTROMETRY; METABOLOMICS; MICROBIAL TRANSLOCATION; MICROBIOLOGICAL PHENOMENA AND FUNCTIONS; MIXED INFECTION; NONALCOHOLIC FATTY LIVER; PROTEIN BINDING; STEROID METABOLISM;

ADULT; BILE ACIDS AND SALTS; BIOLOGICAL MARKERS; COHORT STUDIES; FATTY LIVER; FEMALE; HEPATITIS C; HIV INFECTIONS; HUMANS; INFLAMMATION; LEAST-SQUARES ANALYSIS; LIPID METABOLISM DISORDERS; LIPIDS; MALE; METABOLIC NETWORKS AND PATHWAYS; METABOLOME; METABOLOMICS; MIDDLE AGED; PRINCIPAL COMPONENT ANALYSIS; PROTEASE INHIBITORS;

EID: 84876985996     PISSN: None     EISSN: 14712334     Source Type: Journal    
DOI: 10.1186/1471-2334-13-203     Document Type: Article

References (96)

1. Carr A. HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. AIDS 2003, 17(Suppl 1):S141-148.
2. Brown TT, Glesby MJ. Management of the metabolic effects of HIV and HIV drugs. Nat Rev Endocrinol 2012, 8(1):11-21.
3. Sulkowski MS. Management of hepatic complications in HIV-infected persons. J Infect Dis 2008, 197(Suppl 3):S279-293.
4. Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis 2004, 38(Suppl 2):S90-97.
5. Joshi D, O'Grady J, Dieterich D, Gazzard B, Agarwal K. Increasing burden of liver disease in patients with HIV infection. Lancet 2011, 377(9772):1198-1209. 10.1016/S0140-6736(10)62001-6, 21459211.
6. Guaraldi G, Squillace N, Stentarelli C, Orlando G, D'Amico R, Ligabue G, Fiocchi F, Zona S, Loria P, Esposito R. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis 2008, 47(2):250-257. 10.1086/589294, 18532884.
7. Lemoine M, Serfaty L, Capeau J. From nonalcoholic fatty liver to nonalcoholic steatohepatitis and cirrhosis in HIV-infected patients: diagnosis and management. Curr Opin Infect Dis 2012, 25(1):10-16. 10.1097/QCO.0b013e32834ef599, 22183113.
8. Zylberberg H, Nalpas B, Pol S, Brechot C, Viard JP. Is there a relationship between hepatitis C virus infection and antiretroviral-associated lipoatrophy?. AIDS 2000, 14(13):2055. 10.1097/00002030-200009080-00025, 10997414.
9. Duong M, Petit JM, Piroth L, Grappin M, Buisson M, Chavanet P, Hillon P, Portier H. Association between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy. J Acquir Immune Defic Syndr 2001, 27(3):245-250.
10. Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD, Thomas DL. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS 2005, 19(6):585-592. 10.1097/01.aids.0000163935.99401.25, 15802977.
11. Bani-Sadr F, Carrat F, Bedossa P, Piroth L, Cacoub P, Perronne C, Degott C, Pol S. Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors. AIDS 2006, 20(4):525-531. 10.1097/01.aids.0000210606.63138.f5, 16470116.
12. McGovern BH, Ditelberg JS, Taylor LE, Gandhi RT, Christopoulos KA, Chapman S, Schwartzapfel B, Rindler E, Fiorino AM, Zaman MT. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis 2006, 43(3):365-372. 10.1086/505495, 16804853.
13. Howard AA, Hoover DR, Anastos K, Wu X, Shi Q, Strickler HD, Cole SR, Cohen MH, Kovacs A, Augenbraun M. The effects of opiate use and hepatitis C virus infection on risk of diabetes mellitus in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 2010, 54(2):152-159. 3069645, 20190642.
14. Butt AA, McGinnis K, Rodriguez-Barradas MC, Crystal S, Simberkoff M, Goetz MB, Leaf D, Justice AC. HIV infection and the risk of diabetes mellitus. AIDS 2009, 23(10):1227-1234. 10.1097/QAD.0b013e32832bd7af, 2752953, 19444074.
15. Dai CY, Chuang WL, Ho CK, Hsieh MY, Huang JF, Lee LP, Hou NJ, Lin ZY, Chen SC, Wang LY. Associations between hepatitis C viremia and low serum triglyceride and cholesterol levels: a community-based study. J Hepatol 2008, 49(1):9-16. 10.1016/j.jhep.2008.03.016, 18486265.
16. Cooper CL, Mills E, Angel JB. Mitigation of antiretroviral-induced hyperlipidemia by hepatitis C virus co-infection. AIDS 2007, 21(1):71-76. 10.1097/QAD.0b013e3280110ada, 17148970.
17. Patroni A, Torti C, Tomasoni L, Roldan EQ, Bertelli D, Puoti M, Cadeo GP, Sleiman I, Tinelli C, Carosi G. Effect of highly active antiretroviral therapy (HAART) and hepatitis C Co-infection on hyperlipidemia in HIV-infected patients: a retrospective longitudinal study. HIV Clin Trials 2002, 3(6):451-461. 10.1310/W024-QC4T-NXU0-TKYT, 12501128.
18. Hui JM, Kench J, Farrell GC, Lin R, Samarasinghe D, Liddle C, Byth K, George J. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol 2002, 17(8):873-881. 10.1046/j.1440-1746.2002.02813.x, 12164963.
19. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999, 29(4):1215-1219. 10.1002/hep.510290401, 10094967.
20. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001, 33(6):1358-1364. 10.1053/jhep.2001.24432, 11391523.
21. Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Vallee M, Heaton S, Conrad A, Pockros PJ, McHutchison JG. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol 2004, 40(3):484-490. 10.1016/j.jhep.2003.11.004, 15123364.
22. AACTG) AACTG Table for grading severity of adult adverse experiences 1992, Bethesda, Md: National Institute of Allergy and Infectious Diseases (NIAID), AACTG) AACTG.
23. Johnson CA, Levey AS, Coresh J, Levin A, Lau J, Eknoyan G. Clinical practice guidelines for chronic kidney disease in adults: Part I. Definition, disease stages, evaluation, treatment, and risk factors. Am Fam Physician 2004, 70(5):869-876.
24. Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A, Zaman T, Stone D, Mefford M, Morgello S. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 2008, 3(6):e2516. 10.1371/journal.pone.0002516, 2424175, 18575590.
25. Evans AM, DeHaven CD, Barrett T, Mitchell M, Milgram E. Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem 2009, 81(16):6656-6667. 10.1021/ac901536h, 19624122.
26. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006, 12(12):1365-1371.
27. Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, Contos MJ, Sterling RK, Fuchs M, Zhou H. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 2009, 50(6):1827-1838. 10.1002/hep.23229, 19937697.
28. Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, Milburn M. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism 2011, 60(3):404-413. 10.1016/j.metabol.2010.03.006, 2950914, 20423748.
29. Barr J, Vazquez-Chantada M, Alonso C, Perez-Cormenzana M, Mayo R, Galan A, Caballeria J, Martin-Duce A, Tran A, Wagner C. Liquid chromatography-mass spectrometry-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of nonalcoholic fatty liver disease. J Proteome Res 2010, 9(9):4501-4512. 10.1021/pr1002593, 2933275, 20684516.
30. Shlomai A, Halfon P, Goldiner I, Zelber-Sagi S, Halpern Z, Oren R, Bruck R. Serum bile acid levels as a predictor for the severity of liver fibrosis in patients with chronic hepatitis C. J Viral Hepat 2013, 20(2):95-102. 10.1111/j.1365-2893.2012.01628.x, 23301544.
31. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, SS M, Torriani FJ, Dieterich DT, Thomas DL. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006, 43(6):1317-1325. 10.1002/hep.21178, 16729309.
32. Nunes D, Fleming C, Offner G, Craven D, Fix O, Heeren T, Koziel MJ, Graham C, Tumilty S, Skolnik P. Noninvasive markers of liver fibrosis are highly predictive of liver-related death in a cohort of HCV-infected individuals with and without HIV infection. Am J Gastroenterol 2010, 105(6):1346-1353. 10.1038/ajg.2009.746, 20179698.
33. Shah AG, Smith PG, Sterling RK. Comparison of FIB-4 and APRI in HIV-HCV coinfected patients with normal and elevated ALT. Dig Dis Sci 2011, 56(10):3038-3044. 10.1007/s10620-011-1710-2, 21526398.
34. Resino S, Sanchez-Conde M, Berenguer J. Coinfection by human immunodeficiency virus and hepatitis C virus: noninvasive assessment and staging of fibrosis. Curr Opin Infect Dis 2012, 25(5):564-569. 10.1097/QCO.0b013e32835635df, 22744318.
35. Rath T, Roderfeld M, Guler C, Wenzel C, Graf J, Beitinger F, Roeb E, Zachoval R. YKL-40 and transient elastography, a powerful team to assess hepatic fibrosis. Scand J Gastroenterol 2011, 46(11):1369-1380. 10.3109/00365521.2011.613949, 21905976.
36. Fontana RJ, Dienstag JL, Bonkovsky HL, Sterling RK, Naishadham D, Goodman ZD, Lok AS, Wright EC, Su GL. Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C. Gut 2010, 59(10):1401-1409. 10.1136/gut.2010.207423, 20675691.
37. Fontana RJ, Goodman ZD, Dienstag JL, Bonkovsky HL, Naishadham D, Sterling RK, Su GL, Ghosh M, Wright EC. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology 2008, 47(3):789-798. 10.1002/hep.22099, 18175357.
38. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003, 38(2):518-526. 10.1053/jhep.2003.50346, 12883497.
39. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 2008, 454(7203):470-477. 10.1038/nature07202, 18650918.
40. Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 2005, 25:317-340. 10.1146/annurev.nutr.25.051804.101917, 16011470.
41. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005, 115(5):1111-1119. 1087185, 15864338.
42. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992, 327(5):329-337. 10.1056/NEJM199207303270506, 1620172.
43. Shor-Posner G, Basit A, Lu Y, Cabrejos C, Chang J, Fletcher M, Mantero-Atienza E, Baum MK. Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. Am J Med 1993, 94(5):515-519. 10.1016/0002-9343(93)90087-6, 7605397.
44. Constans J, Pellegrin JL, Peuchant E, Dumon MF, Pellegrin I, Sergeant C, Simonoff M, Brossard G, Barbeau P, Fleury H. Plasma lipids in HIV-infected patients: a prospective study in 95 patients. Eur J Clin Invest 1994, 24(6):416-420. 10.1111/j.1365-2362.1994.tb02185.x, 7957495.
45. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 2007, 7(12):787-796. 10.1016/S1473-3099(07)70287-6, 18045561.
46. Ortiz A, Sanchez-Nino MD. The human plasma lipidome. N Engl J Med 2012, 366(7):668-669. 668; author reply.
47. McRae M, Rezk NL, Bridges AS, Corbett AH, Tien HC, Brouwer KL, Kashuba AD. Plasma bile acid concentrations in patients with human immunodeficiency virus infection receiving protease inhibitor therapy: possible implications for hepatotoxicity. Pharmacotherapy 2010, 30(1):17-24. 10.1592/phco.30.1.17, 2856922, 20030469.
48. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008, 7(8):678-693. 10.1038/nrd2619, 18670431.
49. Sampey BP, Freemerman AJ, Zhang J, Kuan PF, Galanko JA, O'Connell TM, Ilkayeva OR, Muehlbauer MJ, Stevens RD, Newgard CB. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. PLoS One 2012, 7(6):e38812. 10.1371/journal.pone.0038812, 3373493, 22701716.
50. Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, Hwang DH, Newman JW, Garvey WT. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr 2009, 139(6):1073-1081. 10.3945/jn.108.103754, 2714383, 19369366.
51. Shah SH, Bain JR, Muehlbauer MJ, Stevens RD, Crosslin DR, Haynes C, Dungan J, Newby LK, Hauser ER, Ginsburg GS. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ Cardiovasc Genet 2010, 3(2):207-214. 10.1161/CIRCGENETICS.109.852814, 20173117.
52. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008, 7(1):45-56. 10.1016/j.cmet.2007.10.013, 18177724.
53. Noland RC, Koves TR, Seiler SE, Lum H, Lust RM, Ilkayeva O, Stevens RD, Hegardt FG, Muoio DM. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J Biol Chem 2009, 284(34):22840-22852. 10.1074/jbc.M109.032888, 2755692, 19553674.
54. Traish AM, Kang HP, Saad F, Guay AT. Dehydroepiandrosterone (DHEA)-a precursor steroid or an active hormone in human physiology. J Sex Med 2011, 8(11):2960-2982. quiz 2983, 10.1111/j.1743-6109.2011.02523.x, 22032408.
55. Grinspoon SK, Bilezikian JP. HIV disease and the endocrine system. N Engl J Med 1992, 327(19):1360-1365. 10.1056/NEJM199211053271906, 1406838.
56. Christeff N, Melchior JC, de Truchis P, Perronne C, Nunez EA, Gougeon ML. Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations. AIDS 1999, 13(16):2251-2260. 10.1097/00002030-199911120-00007, 10563710.
57. Pachikian BD, Essaghir A, Demoulin JB, Neyrinck AM, Catry E, De Backer FC, Dejeans N, Dewulf EM, Sohet FM, Portois L. Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets. PLoS One 2011, 6(8):e23365. 10.1371/journal.pone.0023365, 3154437, 21853118.
58. Kim SJ, Zhang Z, Saha A, Sarkar C, Zhao Z, Xu Y, Mukherjee AB. Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1. Neurosci Lett 2010, 479(3):292-296. 10.1016/j.neulet.2010.05.083, 2904481, 20561933.
59. Pachikian BD, Neyrinck AM, Cani PD, Portois L, Deldicque L, De Backer FC, Bindels LB, Sohet FM, Malaisse WJ, Francaux M. Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition. BMC Physiol 2008, 8:21. 10.1186/1472-6793-8-21, 2612019, 19046413.
60. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004, 4(10):762-774. 10.1038/nri1457, 15459668.
61. Murray MF. Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. Lancet Infect Dis 2003, 3(10):644-652. 10.1016/S1473-3099(03)00773-4, 14522263.
62. Favre D, Mold J, Hunt PW, Kanwar B, Loke P, Seu L, Barbour JD, Lowe MM, Jayawardene A, Aweeka F. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2010, 2(32):32-36.
63. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008, 8(5):349-361. 10.1038/nri2294, 2744593, 18437155.
64. Blanc M, Hsieh WY, Robertson KA, Watterson S, Shui G, Lacaze P, Khondoker M, Dickinson P, Sing G, Rodriguez-Martin S. Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol 2011, 9(3):e1000598. 10.1371/journal.pbio.1000598, 3050939, 21408089.
65. Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell 2003, 12(4):805-816. 10.1016/S1097-2765(03)00384-8, 14580333.
66. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 1994, 93(5):2114-2119. 10.1172/JCI117206, 294340, 8182142.
67. Dasgupta B, Corkill M, Kirkham B, Gibson T, Panayi G. Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. J Rheumatol 1992, 19(1):22-25.
68. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995, 332(5):305-311. 10.1056/NEJM199502023320506, 7816067.
69. Ikeda U, Ikeda M, Seino Y, Takahashi M, Kano S, Shimada K. Interleukin 6 gene transcripts are expressed in atherosclerotic lesions of genetically hyperlipidemic rabbits. Atherosclerosis 1992, 92(2-3):213-218.
70. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett 1995, 202(1-2):17-20.
71. Wood JA, Wood PL, Ryan R, Graff-Radford NR, Pilapil C, Robitaille Y, Quirion R. Cytokine indices in Alzheimer's temporal cortex: no changes in mature IL-1 beta or IL-1RA but increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive protein. Brain Res 1993, 629(2):245-252. 10.1016/0006-8993(93)91327-O, 7509248.
72. Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998, 83(6):2012-2017. 10.1210/jc.83.6.2012, 9626133.
73. Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY. Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol 1993, 150(12):5219-5230.
74. Blackard JT, Welge JA, Taylor LE, Mayer KH, Klein RS, Celentano DD, Jamieson DJ, Gardner L, Sherman KE. HIV mono-infection is associated with FIB-4 - A noninvasive index of liver fibrosis - in women. Clin Infect Dis 2011, 52(5):674-680. 10.1093/cid/ciq199, 3106241, 21248367.
75. Berres ML, Papen S, Pauels K, Schmitz P, Zaldivar MM, Hellerbrand C, Mueller T, Berg T, Weiskirchen R, Trautwein C. A functional variation in CHI3L1 is associated with severity of liver fibrosis and YKL-40 serum levels in chronic hepatitis C infection. J Hepatol 2009, 50(2):370-376. 10.1016/j.jhep.2008.09.016, 19070929.
76. Tran A, Benzaken S, Saint-Paul MC, Guzman-Granier E, Hastier P, Pradier C, Barjoan EM, Demuth N, Longo F, Rampal P. Chondrex (YKL-40), a potential new serum fibrosis marker in patients with alcoholic liver disease. Eur J Gastroenterol Hepatol 2000, 12(9):989-993. 10.1097/00042737-200012090-00004, 11007134.
77. Mannes GA, Thieme C, Stellaard F, Wang T, Sauerbruch T, Paumgartner G. Prognostic significance of serum bile acids in cirrhosis. Hepatology 1986, 6(1):50-53. 10.1002/hep.1840060110, 3943790.
78. Hoppel C. The role of carnitine in normal and altered fatty acid metabolism. American j kidney dis official j National Kidney Foundation 2003, 41(4 Suppl 4):S4-12.
79. Spivey JR, Bronk SF, Gores GJ. Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium. J Clin Invest 1993, 92(1):17-24. 10.1172/JCI116546, 293519, 8325981.
80. Krahenbuhl S, Fischer S, Talos C, Reichen J. Ursodeoxycholate protects oxidative mitochondrial metabolism from bile acid toxicity: dose-response study in isolated rat liver mitochondria. Hepatology 1994, 20(6):1595-1601. 10.1002/hep.1840200632, 7982660.
81. Krahenbuhl S, Talos C, Fischer S, Reichen J. Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 1994, 19(2):471-479.
82. Rolo AP, Oliveira PJ, Moreno AJ, Palmeira CM. Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy. Toxicol sci official j Society Toxicol 2000, 57(1):177-185.
83. Korman MG, Hofmann AF, Summerskill WH. Assessment of activity in chronic active liver disease. Serum bile acids compared with conventional tests and histology. N Engl J Med 1974, 290(25):1399-1402. 10.1056/NEJM197406202902503, 4133590.
84. Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol 1987, 4(1):8-14. 10.1016/S0168-8278(87)80003-X, 3571935.
85. Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm (Lond) 2010, 7:15.
86. Caradonna L, Amati L, Magrone T, Pellegrino NM, Jirillo E, Caccavo D. Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J Endotoxin Res 2000, 6(3):205-214.
87. Sandler NG, Koh C, Roque A, Eccleston JL, Siegel RB, Demino M, Kleiner DE, Deeks SG, Liang TJ, Heller T. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011, 141(4):1220-1230. 1230 e1221-1223, 10.1053/j.gastro.2011.06.063, 3186837, 21726511.
88. Hofer U, Schlaepfer E, Baenziger S, Nischang M, Regenass S, Schwendener R, Kempf W, Nadal D, Speck RF. Inadequate clearance of translocated bacterial products in HIV-infected humanized mice. PLoS Pathog 2010, 6(4):e1000867. 10.1371/journal.ppat.1000867, 2861703, 20442871.
89. Cabre E, Gassull MA. Polyunsaturated fatty acid deficiency in liver diseases: pathophysiological and clinical significance. Nutrition 1996, 12(7-8):542-548.
90. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002, 287(3):356-359. 10.1001/jama.287.3.356, 11790215.
91. Wagner M, Zollner G, Trauner M. Nuclear receptors in liver disease. Hepatology 2011, 53(3):1023-1034. 10.1002/hep.24148, 21319202.
92. Mencarelli A, Cipriani S, Renga B, Francisci D, Palladino G, Distrutti E, Baldelli F, Fiorucci S. The bile acid sensor FXR protects against dyslipidemia and aortic plaques development induced by the HIV protease inhibitor ritonavir in mice. PLoS One 2010, 5(10):e13238. 10.1371/journal.pone.0013238, 2951893, 20949026.
93. Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 2010, 51(4):771-784. 10.1194/jlr.M001602, 2842143, 19783811.
94. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, Wand H, Law M, Samaras K, Emery S. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 2004, 363(9407):429-438. 10.1016/S0140-6736(04)15489-5, 14962523.
95. Slama L, Lanoy E, Valantin MA, Bastard JP, Chermak A, Boutekatjirt A, William-Faltaos D, Billaud E, Molina JM, Capeau J. Effect of pioglitazone on HIV-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (ANRS 113). Antivir Ther 2008, 13(1):67-76.
96. Walli R, Michl GM, Muhlbayer D, Brinkmann L, Goebel FD. Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus. Res Exp Med (Berl) 2000, 199(5):253-262.