Clinical physiology of NAFLD: A critical overview of pathogenesis and treatment

Expert Review of Endocrinology and Metabolism

Volumn 5, Issue 3, 2010, Pages 403-423

  Lonardo, Amedeo ^a   Caldwell, Stephen H ^b   Loria, Paola ^a  

^a Nuovo Ospedale S Agostino   (Italy)

^b UNIVERSITY OF VIRGINIA   (United States)

Author keywords

Adipose tissue; Alcohol; Diet; Exercise; Fructose; Hypothalamus; Insulin resistance; Metabolic syndrome; Mitochondria; Molecular mechanism; Muscle; Natural history; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Pathogenesis; Treatment

Indexed keywords

1 [5 HYDROXY 2 (2 THIENYL) 4 QUINAZOLINYLAMINO] 3 METHYL 2,5 PYRROLEDIONE; 2,4 THIAZOLIDINEDIONE DERIVATIVE; ALPHA TOCOPHEROL; AQUAPORIN; ASCORBIC ACID; BILE ACID; CARBENOXOLONE; CLOFIBRATE; EXENDIN 4; EZETIMIBE; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; HIGH DENSITY LIPOPROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN; LOW DENSITY LIPOPROTEIN; METFORMIN; NEOMYCIN; PENTOXIFYLLINE; PIOGLITAZONE; POLYMYXIN B; PROBIOTIC AGENT; PROBUCOL; RESVERATROL; RIMONABANT; ROSIGLITAZONE; TELMISARTAN; TETRAHYDROLIPSTATIN; UNINDEXED DRUG; VERY LOW DENSITY LIPOPROTEIN;

ALCOHOL CONSUMPTION; ANXIETY; BARIATRIC SURGERY; BODY FAT DISTRIBUTION; CALORIC RESTRICTION; DEPRESSION; DYSLIPIDEMIA; ENERGY BALANCE; ETHNIC DIFFERENCE; EXERCISE; GENETIC SUSCEPTIBILITY; GLUCOSE HOMEOSTASIS; HUMAN; HYPERGLYCEMIA; INFLAMMATION; INSULIN RESISTANCE; INSULIN SENSITIVITY; INTESTINE FLORA; KUPFFER CELL; LIFESTYLE MODIFICATION; LIPOSUCTION; MEDITERRANEAN DIET; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; WEIGHT GAIN; WEIGHT REDUCTION; WHITE ADIPOSE TISSUE;

EID: 77952517940     PISSN: 17446651     EISSN: None     Source Type: Journal    
DOI: 10.1586/eem.10.5     Document Type: Review

References (254)

1. Loria P, Lonardo A, Carulli L et al. Review article: the metabolic syndrome and non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 22 (Suppl. 2), 31-36 (2005).
2. Cowey S, Hardy RW. The metabolic syndrome: a high-risk state for cancer? Am. J. Pathol. 169, 1505-1522 (2006).
3. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J. Androl. 30, 10-22 (2009).
4. Razani B, Chakravarthy MV, Semenkovich CF. Insulin resistance and atherosclerosis. Endocrinol. Metab. Clin. North Am. 37, 603-621, viii (2008).
5. Tsouli SG, Liberopoulos EN, Mikhailidis DP, Athyros VG, Elisaf MS. Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander? Metabolism 55, 1293-1301 (2006).
6. Cirillo P, Sautin Y Y, Kanellis J et al. Systemic inflammation, metabolic syndrome and progressive renal disease. Nephrol. Dial. Transplant. 24, 1384-1387 (2009).
7. Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. Semin. Thromb. Hemost. 35, 277-287 (2009).
8. Pereira RM, de Carvalho JF, Bonfá E. Metabolic syndrome in rheumatological diseases. Autoimmun. Rev. 8, 415-419 (2009).
9. Trombini P, Piperno A. Ferritin, metabolic syndrome and NAFLD: elective attractions and dangerous liaisons. J. Hepatol. 46, 549-552 (2007).
10. Calvin AD, Albuquerque FN, Lopez-Jimenez F, Somers VK. Obstructive sleep apnea, inflammation, and the metabolic syndrome. Metab. Syndr. Relat. Disord. 7, 271-278 (2009).
11. Grundy SM. Cholesterol gallstones: a fellow traveler with metabolic syndrome? Am. J. Clin. Nutr. 80, 1-2 (2004).
12. Boyko EJ, Leonetti DL, Bergstrom RW, Newell-Morris L, Fujimoto WY. Low insulin secretion and high fasting insulin and C-peptide levels predict increased visceral adiposity. 5-year follow-up among initially nondiabetic Japanese-American men. Diabetes 45, 1010-1015 (1996).
13. Lonardo A, Carani C, Carulli N, Loria P. Chicken or egg turned into head or belly. J. Hepatol. 45, 454-456 (2006).
14. Tong J, Fujimoto WY, Kahn SE et al. Insulin, C-peptide, and leptin concentrations predict increased visceral adiposity at 5- and 10-year follow-ups in nondiabetic Japanese Americans. Diabetes 54, 985-990 (2005).
15. Chrousos GP. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Int. J. Obes. Relat. Metab. Disord. 24 (Suppl. 2), S50-S55 (2000).
16. Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 28, 27-38 (2008).
17. Loria P, Lonardo A, Targher G. Is liver fat detrimental to vessels?: intersections in the pathogenesis of NAFLD and atherosclerosis. Clin. Sci. (Lond). 115, 1-12 (2008).
18. Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia 51, 1947-1953 (2008).
19. Diehl AM, Goodman Z, Ishak KG. Alcohol like liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology 95, 1056-1062 (1988).
20. Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology 129, 375-378 (2005).
21. Michelini E, Lonardo A, Ballestri S et al. Is cholangiocarcinoma another complication of insulin resistance: a report of three cases. Metab. Syndr. Relat. Disord. 5, 194-202 (2007).
22. Baik I, Shin C. Prospective study of alcohol consumption and metabolic syndrome. Am. J. Clin. Nutr. 87, 1455-1463 (2008).
23. Albano E. New concepts in the pathogenesis of alcoholic liver disease. Expert Rev. Gastroenterol. Hepatol. 2, 749-759 (2008).
24. Ferrannini E, Balkau B, Coppack SW et al. RISC Investigators. Insulin resistance, insulin response, and obesity as indicators of metabolic risk. J. Clin. Endocrinol. Metab. 92, 2885-2892 (2007).
25. Ferrannini E. Metabolic syndrome: a solution in search of a problem. J. Clin. Endocrinol. Metab. 92, 396-398 (2007).
26. Bajaj M, Defronzo RA. Metabolic and molecular basis of insulin resistance. J. Nucl. Cardiol. 10, 311-323 (2003).
27. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and Type 2 diabetes. Nature 444, 840-846 (2006).
28. Ferrannini E. Insulin resistance, iron, and the liver. Lancet 355, 2181-2182 (2000).
29. Hücking K, Watanabe RM, Stefanovski D, Bergman RN. OGTT-derived measures of insulin sensitivity are confounded by factors other than insulin sensitivity itself. Obesity (Silver Spring) 16, 1938-1945 (2008).
30. Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 24, 539-548 (2001).
31. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22, 1462-1470 (1999).
32. Gutt M, Davis CL, Spitzer SB et al. Validation of the insulin sensitivity index (ISI (0, 120)): comparison with other measures. Diabetes Res. Clin. Pract. 47, 177-184 (2000).
33. Bonora E, Targher G, Alberiche M et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23, 57-63 (2000).
34. Yki-Järvinen H, Westerbacka J. The fatty liver and insulin resistance. Curr. Mol. Med. 5, 287-295 (2005).
35. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with Type 2 diabetes. Diabetes 54 (3), 603-608 (2005). Demonstrates that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled Type 2 diabetes by mobilizing a relatively small pool of intrahepatic lipidic content, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.
36. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 27, 1487-1495 (2004).
37. Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Järvinen H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in Type 2 diabetes. Gastroenterology 135, 122-130 (2008).
38. Tirone TA, Brunicardi FC. Overview of glucose regulation. World J. Surg 25, 461-467 (2001).
39. Kantartzis K, Machicao F, Machann J et al The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans. Clin. Sci. (Lond). 116, 531-537 (2009).
40. Lonardo A, Lombardini S, Scaglioni F et al. Hepatic steatosis and insulin resistance: does etiology make a difference? J. Hepatol. 44, 190-196 (2006). γ-glutamyltranspeptidase rather than steatosis is correlated with insulin resistance in patients with steatosis owing to varying etiologies (nonalcoholic fatty liver disease [NAFLD], hepatitis C infection and genetic hypobetalipoproteinemia).
41. Cotrim HP, Carvalho F, Siqueira AC, Lordelo M, Rocha R, De Freitas LA. Nonalcoholic fatty liver and insulin resistance among petrochemical workers. JAMA 294, 1618-1620 (2005).
42. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134, 1369-1375 (2008).
43. Cheung O, Kapoor A, Puri P et al. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome. Hepatology 46, 1091-1100 (2007). While waist circumference predicts the profile of metabolic risk, dorsicervical lipohypertrophy is most strongly associated with severity of steatohepatitis.
44. Ballestri S. The neck-liver axis. Madelung disease as further evidence for an impact of body fat distribution on hepatic histology Hepatology 47, 361-362 (2008).
45. Grunfeld C, Rimland D, Gibert CL et al. Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study. J. Acquir. Immune Defc. Syndr. 46, 283-290 (2007).
46. Perseghin G, Lattuada G, De Cobelli F et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47, 51-58 (2008).
47. Iacobellis G, Leonetti F. Epicardial adipose tissue and insulin resistance in obese subjects. J. Clin. Endocrinol. Metab. 90, 6300-6302 (2005).
48. Lonardo A, Loria P, Carulli N. Concurrent non-alcoholic steatohepatitis and psoriasis. Report of three cases from the POLI. STE. N. A. study. Dig. Liver Dis. 33, 86-87 (2001).
49. Gottlieb AB, Dann F, Menter A. Psoriasis and the metabolic syndrome. J. Drugs Dermatol. 7, 563-572 (2008).
50. Mailler-Savage EA, Adams BB. Exogenous insulin-derived acanthosis nigricans. Arch. Dermatol. 144, 126-127 (2008).
51. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 42, 987-1000 (2005). In-depth review of insulin resistance in the pathophysiology and treatment of NAFLD.
52. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 35, 898-904 (2002).
53. Lonardo A, Loria P. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 36, 514-515 (2002).
54. Ginsberg HN. Efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia. J. Clin. Endocrinol. Metab. 91, 383-392 (2006).
55. Toledo FG, Sniderman AD, Kelley DE. Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in Type 2 diabetes. Diabetes Care 29 (8), 1845-1850 (2006).
56. Kantartzis K, Rittig K, Cegan A et al. Fatty liver is independently associated with alterations in circulating HDL2 and HDL3 subfractions. Diabetes Care 31, 366-368 (2008).
57. Petersen KF, Dufour S, Savage DB et al The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl Acad. Sci. USA 104, 12587-12594 (2007). Clearly demonstrates that insulin resistance in skeletal muscle, owing to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in atherogenic dyslipidemia.
58. 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. 115, 1343-1351 (2005). Seminal gas chromatography/mass spectrometry study demonstrating, in humans, that approximately 60% of triglycerides within the liver arise from nonesterified circulating; nearly a quarter from de novo lipogenesis and only 15% from the diet.
59. 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 134, 424-431 (2008).
60. Tarugi P, Lonardo A, Ballarini G et al Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology 111, 1125-1133 (1996).
61. Wildman RP, Muntner P, Reynolds K et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch. Intern. Med. 168, 1617-1624 (2008).
62. Paterson JM, Morton NM, Fievet C et al Metabolic syndrome without obesity: hepatic overexpression of 11β-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc. Natl Acad. Sci. USA 101, 7088-7093 (2004).
63. Stefan N, Kantartzis K, Machann J et al Identification and characterization of metabolically benign obesity in humans. Arch. Intern. Med. 168, 1609-1616 (2008). Provides evidence for the existence of a metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis in humans.
64. Imai J, Katagiri H, Yamada T et al. Regulation of pancreatic β cell mass by neuronal signals from the liver. Science 322, 1250-1254 (2008).
65. Caldwell SH, Ikura Y, Iezzoni JC, Liu Z. Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver) ? J. Gastroenterol. Hepatol 22 (Suppl. 1), S11-S19 (2007).
66. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796-1808 (2003).
67. Xu H, Barnes GT, Yang Q et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821-1830 (2003). Provides direct evidence for the theory that macrophages in white adipose tissue play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.
68. Curat CA, Miranville A, Sengenes C et al From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 53, 1285-1292 (2004).
69. Cancello R, Henegar C, Viguerie N et al Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54, 2277-2286 (2005).
70. Bornstein SR, Abu-Asab M, Glasow A et al Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. Diabetes 49, 532-538 (2000).
71. Cinti S, Mitchell G, Barbatelli G et al Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347-2355 (2005).
72. Stienstra R, Duval C, Muller M, Kersten S. PPARs, obesity, and inflammation. PPAR Res. 2007, 95974 (2007).
73. Ebstein W. Zur therapie des Diabetes mellitus, insbesondere über die Anwendung des salicylsauren Natron bei demselben. Berliner Klinische Wochenschrift. 13, 337-340 (1876).
74. Day CP, James OF. Steatohepatitis: a tale of two 'hits'? Gastroenterology 114, 842-845 (1998).
75. Dam-Larsen S, Franzmann M, Andersen IB et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 53, 750-755 (2004).
76. Ekstedt M, Franzén LE, Mathiesen UL et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865-873 (2006).
77. Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J. Hepatol. 51 (1), 212-223 (2009).
78. Alkerwi A, Boutsen M, Vaillant M et al Alcohol consumption and the prevalence of metabolic syndrome: a meta-analysis of observational studies. Atherosclerosis 204, 624-635 (2009).
79. Loria P, Lonardo A, Carulli N. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 39, 1748 (2004).
80. Ratziu V, Bellentani S, Cortez-Pinto H, Day CP, Marchesini G. A Position Statement on NAFLD/NASH Based on the EASL 2009 Special Conference. J. Hepatol. (2010) (In press).
81. Arrese M. Burning hepatic fat: therapeutic potential for liver-specific thyromimetics inthe treatment of nonalcoholic fatty liver disease. Hepatology 49, 348-351 (2009).
82. Cusi K. Nonalcoholic fatty liver disease in Type 2 diabetes mellitus. Curr. Opin. Endocrinol. Diabetes Obes. 16, 141-149 (2009).
83. Farrell GC. The liver and the waistline: fifty years of growth. J. Gastroenterol. Hepatol. 24 (Suppl. 3), S105-S118 (2009).
84. Yamauchi T, Kamon J, Minokoshi Y et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288-1295 (2002).
85. Stefan N, Machicao F, Staiger H et al. Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia 48, 2282-2291 (2005).
86. Bugianesi E, Pagotto U, Manini R et al. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J. Clin. Endocrinol. Metab. 90, 3498-3504 (2005).
87. Kantartzis K, Rittig K, Balletshofer B et al. The relationships of plasma adiponectin with a favorable lipid profile, decreased inflammation, and less ectopic fat accumulation depend on adiposity. Clin. Chem. 52, 1934-1942 (2006).
88. Kantartzis K, Staiger H, Machann J et al. Adiponectin oligomers and ectopic fat in liver and skeletal muscle in humans. Obesity (Silver Spring) 17, 390-392 (2009).
89. Nannipieri M, Cecchetti F, Anselmino M et al. Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis. Obes. Surg. 19, 467-474 (2009).
90. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology 131, 934-945 (2006).
91. Tamura Y, Sugimoto M, Murayama T et al. Inhibition of CCR2 ameliorates insulin resistance and hepatic steatosis in db/db mice. Arterioscler. Thromb. Vasc. Biol. 28, 2195-2201 (2008).
92. Barbuio R, Milanski M, Bertolo MB, Saad MJ, Velloso LA. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J. Endocrinol. 194, 539-550 (2007).
93. Hotamisligil GS. Inflammation and metabolic disorders. Nature 444, 860-867 (2006). Seminal papers highlighting the evolutionary and basic integrations between metabolic and immune systems, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, Type 2 diabetes and cardiovascular disease.
94. Bäckhed F, Ding H, Wang T et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718-15723 (2004).
95. Samuel BS, Shaito A, Motoike T et al Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767-16772 (2008).
96. Miele L, Valenza V, La Torre G et al Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877-1887 (2009). Provides the first evidence that NAFLD in humans is associated with disruption of intercellular tight junctions, increased gut permeability and increased prevalence of small intestinal bacterial overgrowth.
97. Farrell GC. Is bacterial ash the flash that ignites NASH? Gut 48, 148-149 (2001).
98. Vanni E, Bugianesi E. The gut-liver axis in nonalcoholic fatty liver disease: another pathway to insulin resistance? Hepatology 49, 1790-1792 (2009).
99. Avram AS, Avram MM, James WD. Subcutaneous fat in normal and diseased states: 2. Anatomy and physiology of white and brown adipose tissue. J. Am. Acad. Dermatol. 53, 671-683 (2005).
100. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 131, 242-256 (2007).
101. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM et al Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500-1508 (2009). Demonstrates that a reduced activity in brown adipose tissue may be a contributor to being overweight or obesity, generating a stimulating debate in the medical community.
102. Morino K, Petersen KF, Dufour S et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of Type 2 diabetic parents. J. Clin. Invest. 115, 3587-3593 (2005).
103. Caldwell SH, Chang CY, Nakamoto RK, Krugner-Higby L. Mitochondria in nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 595-617 (2004).
104. Stefan N, Thamer C, Staiger H et al. Genetic variations in PPARD and PPARGC1A determine mitochondrial function and change in aerobic physical fitness and insulin sensitivity during lifestyle intervention. J. Clin. Endocrinol. Metab. 92, 1827-1833 (2007).
105. Thamer C, Machann J, Stefan N et al. High visceral fat mass and high liver fat are associated with resistance to lifestyle intervention. Obesity (Silver Spring) 15, 531-538 (2007).
106. Caldwell SH, Harris DM, Patrie JT, Hespenheide EE. Is NASH underdiagnosed among African Americans? Am. J. Gastroenterol. 97, 1496-1500 (2002). Far-seeing clinical study demonstrating that, although over-represented among patients with major risk factors for nonalcoholic steatohepatitis (NASH), individuals of African-American descent might be spared from NASH or cryptogenic cirrhosis.
107. Browning JD, Szczepaniak LS, Dobbins R et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity Hepatology 40, 1387-1395 (2004).
108. Weston SR, Leyden W, Murphy R et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 41, 372-379 (2005).
109. Solga SF, Clark JM, Alkhuraishi AR et al. Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients. Surg. Obes. Relat. Dis. 1, 6-11 (2005).
110. Giday SA, Ashiny Z, Naab T, Smoot D, Banks A. Frequency of nonalcoholic fatty liver disease and degree of hepatic steatosis in African-American patients. J. Natl Med. Assoc. 98, 1613-1615 (2006).
111. Kallwitz ER, Kumar M, Aggarwal R et al. Ethnicity and nonalcoholic fatty liver disease in an obesity clinic: the impact of triglycerides. Dig. Dis. Sci. 53, 1358-1363 (2008).
112. Kallwitz ER, Guzman G, TenCate V et al. The histologic spectrum of liver disease in African-American, non-Hispanic white, and Hispanic obesity surgery patients. Am. J. Gastroenterol. 104, 64-69 (2009).
113. Mohanty SR, Troy TN, Huo D, O'Brien BL, Jensen DM, Hart J. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J. Hepatol. 50, 797-804 (2009).
114. Riquelme A, Arrese M, Soza A et al. Non-alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C-reactive protein in Hispanics. Liver Int. 29, 82-88 (2009).
115. Schwimmer JB, McGreal N, Deutsch R, Finegold MJ, Lavine JE. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics 115, e561-e565 (2005).
116. Leung DH, Williams K, Fraley JK, Klish WJ. Age- and ethnic-specific elevation of ALT among obese children at risk for nonalcoholic steatohepatitis (NASH): implications for screening. Clin. Pediatr. (Phila). 48, 50-57 (2009).
117. Romeo S, Kozlitina J, Xing C et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465 (2008).
118. Kotronen A, Peltonen M, Hakkarainen A et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 137, 865-872 (2009). Reports the NAFLD liver fat score and liver fat equation that provide simple and noninvasive tools to predict NAFLD and liver fat content in clinical practice.
119. Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 49, 791-801 (2009). African-Americans appear to be more resistant to both the accretion of triglyceride in the adipose tissue and liver, and hypertriglyceridemia associated with insulin resistance compared with Hispanics or Caucasians.
120. Sumner AE, Kushner H, Tulenko TN, Falkner B, Marsh JB. The relationship in African-Americans of sex differences in insulin-mediated suppression of nonesterified fatty acids to sex differences in fasting triglyceride levels. Metabolism 46, 400-405 (1997).
121. Hatta H, Atomi Y, Shinohara S, Yamamoto Y, Yamada S. The effects of ovarian hormones on glucose and fatty acid oxidation during exercise in female ovariectomized rats. Horm. Metab. Res. 20, 609-611 (1988).
122. Dixon JB, Bhathal PS, Jonsson JR, Dixon AF, Powell EE, O'Brien PE. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J. Hepatol. 39, 967-971 (2003).
123. Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J. Hepatol. 46, 1104-1110 (2007).
124. Sazci A, Akpinar G, Aygun C, Ergul E, Senturk O, Hulagu S. Association of apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis. Dig. Dis. Sci. 53, 3218-3224 (2008).
125. Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Hepatology 47, 1167-1177 (2008).
126. Musso G, Gambino R, Pacini G, Pagano G, Durazzo M, Cassader M. Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH. Hepatology 49, 426-435 (2009).
127. Tokushige K, Hashimoto E, Noto H et al. Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease. J. Gastroenterol. 44, 976-982 (2009).
128. Carulli L, Canedi I, Rondinella S et al. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with nonalcoholic steatohepatitis. Dig. Liver Dis. 41, 823-828 (2009).
129. Steele RM, Brage S, Corder K, Wareham NJ, Ekelund U. Physical activity, cardiorespiratory fitness, and the metabolic syndrome in youth. J. Appl. Physiol. 105, 342-351 (2008).
130. Hassinen M, Lakka TA, Savonen K et al. Cardiorespiratory fitness as a feature of metabolic syndrome in older men and women: the Dose-Responses to Exercise Training study (DR's EXTRA). Diabetes Care 31, 1242-1247 (2008). Provides evidence for low cardiorespiratory fitness as a feature of the metabolic syndrome.
131. Neuschwander-Tetri BA. Food energy efficiency, cannabinoids, and a slow death of the weight loss dogma. Hepatology 46, 12-15 (2007).
132. Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J. Appl. Physiol. 99, 2008-2019 (2005).
133. Jesudason D, Wittert G. Endocannabinoid system in food intake and metabolic regulation. Curr. Opin. Lipidol. 19, 344-348 (2008).
134. Cortez-Pinto H, Machado M. Previous practice of high-intensity sports as a risk factor for non-alcoholic steatohepatitis. Liver Int. 28, 412-414 (2008).
135. Kantartzis K, Thamer C, Peter A et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 58, 1281-1288 (2009).
136. Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J. Postic ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J. Clin. Invest. 118, 956-964 (2008).
137. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G987-Gp995 (2008).
138. Osei-Hyiaman D, Liu J, Zhou L et al. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J. Clin. Invest. 118, 3160-3169 (2008).
139. Ahima RS. Insulin resistance: cause or consequence of nonalcoholic steatohepatitis? Gastroenterology 132, 444-446 (2007).
140. Suzuki A, Angulo P, Lymp J et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 41, 64-71 (2005).
141. Kotronen A, Westerbacka J, Bergholm R et al. Liver fat in the metabolic syndrome. J. Clin. Endocrinol. Metab. 92, 3490-3497 (2007). Liver fat content is significantly increased in subjects with the metabolic syndrome, independent of age, gender and BMI.
142. Sattar N, McConnachie A, Ford I et al Serial metabolic measurements and conversion to Type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor. Diabetes 56, 984-991 (2007).
143. Kotronen A, Juurinen L, Hakkarainen A et al. Liver fat is increased in Type 2 diabetic patients and underestimated by serum alanine minotransferase compared with equally obese nondiabetic subjects. Diabetes Care 31, 165-169 (2008). Type 2 diabetic patients have 80% more liver fat than age-, weight- and sexmatched nondiabetic subjects.
144. Dunbar JA, Reddy P, Davis-Lameloise N et al. Depression: an important comorbidity with metabolic syndrome in a general population. Diabetes Care 31, 2368-2373 (2008).
145. Takeuchi T, Nakao M, Nomura K, Yano E. Association of metabolic syndrome with depression and anxiety in Japanese men. Diabetes Metab. 35, 32-36 (2009).
146. Vanhala M, Jokelainen J, Keinänen-Kiukaanniemi S, Kumpusalo E, Koponen H. Depressive symptoms predispose females to metabolic syndrome: a 7-year follow-up study. Acta Psychiatr. Scand. 119, 137-142 (2009).
147. Loria P, Carulli L, Bertolotti M, Lonardo A. Endocrine and liver interaction: the role of endocrine pathways in NASH. Nat. Rev. Gastroenterol. Hepatol. 6, 236-247 (2009). Reviews the evidence for a role of hormonal disorders in the etiopathogenesis of NASH.
148. Lam TK, Gutierrez-Juarez R, Pocai A et al Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat. Med. 13, 171-180 (2007).
149. Benoit SC, Kemp CJ, Elias CF et al Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents. J. Clin. Invest. 119, 2577-2589 (2009). Study suggests that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS-mediated via PKC-θ activation, resulting in reduced insulin activity.
150. Martínez de Morentin PB, Varela L, Fernø J et al. Hypothalamic lipotoxicity and the metabolic syndrome. Biochim. Biophys. Acta (2009).
151. Velloso LA, Araújo EP, de Souza CT Diet-induced inflammation of the hypothalamus in obesity Neuroimmunomodulation 15, 189-193 (2008).
152. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKβ NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61-73 (2008).
153. Mofrad P, Contos MJ, Haque M et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37, 1286-1292 (2003).
154. Fracanzani AL, Valenti L, Bugianesi E et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 48, 792-798 (2008).
155. Burke A, Lucey MR. Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation. Am. J. Transplant. 4, 686-693 (2004).
156. Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes. Rev. DOI: 10.1111/j.1467-789X.2009. 00657 (2009) (Epub ahead of print).
157. Yamaguchi K, Yang L, McCall S et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366-1374 (2007). Treating mice, fed a diet deficient in methionine and choline, with diacylglycerol acyltransferase 2 antisense oligonucleotide for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation and fibrosis.
158. Kantartzis K, Machicao F, Machann J et al. The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans. Clin. Sci. (Lond). 116, 531-537 (2009).
159. Perra A, Simbula G, Simbula M et al Thyroid hormone (T3) and TRβ agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 22, 2981-2989 (2008).
160. Hardie DG. Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 582, 81-89 (2008).
161. Lomb DJ, Laurent G, Haigis MC. Sirtuins regulate key aspects of lipid metabolism. Biochim. Biophys. Acta DOI: 10.1016/j.bbapap. 2009.11.021 (2010) (Epub ahead of print).
162. Satapathy SK, Garg S, Chauhan R et al. Beneficial effects of tumor necrosis factor-a inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with non-alcoholic steatohepatitis. Am. J. Gastroenterol. 99, 1946-1952 (2004).
163. Rinella ME, Koppe S, Brunt EM, Elias M, Gottstein J, Green RM. Pentoxiphylline improves ALT and histology in patients with NASH: a double-blind placebo controlled trial. Gastroenterology 136 (Suppl. DDW), 213 (2009).
164. Beraza N, Malato Y, Vander Borght S et al. Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 57, 655-663 (2008).
165. Thamer C, Machann J, Stefan N et al. Variations in PPARD determine the change in body composition during lifestyle intervention: a whole-body magnetic resonance study. J. Clin. Endocrinol. Metab. 93, 1497-1500 (2008).
166. Bellentani S, Dalle Grave R, Suppini A, Marchesini G. Fatty Liver Italian Network. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology 47, 746-754 (2008). Principles of behavior therapy are presented in detail. A brief section is also included on the practical aspects and public policies to be implemented at a community level to obtain the maximum effects in lifestyle changes.
167. Hamaguchi M, Kojima T, Takeda N et al The metabolic syndrome as a predictor of onalcoholic fatty liver disease. Ann. Intern. Med. 143, 722-728 (2005).
168. Suzuki A, Lindor K, St Saver J et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J. Hepatol. 43, 1060-1066 (2005).
169. Chang Y, Ryu S, Sung E, Woo HY, Cho SI, Yoo SH. Weight gain within the normal weight range predicts nonalcoholic fatty liver disease in healthy Korean men. Gut 58, 1419-1425 (2009).
170. Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 136, 1552-1560 (2009).
171. Andersen T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese subjects. J. Hepatol. 12, 224-229 (1991).
172. Esposito K, Marfella R, Ciotola M et al Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 292, 1440-1446 (2004).
173. Zivkovic AM, German JB, Sanyal AJ. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am. J. Clin. Nutr. 86, 285-300 (2007).
174. Ricchi M, Odoardi MR, Carulli L et al Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J. Gastroenterol Hepatol. 24, 830-840 (2009).
175. Johnson RJ, Perez-Pozo SE, Sautin YY et al. Hypothesis: could excessive fructose intake and uric acid cause Type 2 diabetes? Endocr. Rev. 30, 96-116 (2009).
176. Ouyang X, Cirillo P, Sautin Y et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J. Hepatol 48, 993-999 (2008).
177. Spruss A, Bergheim I. Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease. J. Nutr. Biochem. 20, 657-662 (2009).
178. Suzuki A, Angulo P, St Sauver J, Muto A, Okada T, Lindor K. Light to moderate alcohol consumption is associated with lower frequency of hypertransaminasemia. Am. J. Gastroenterol. 102, 1912-1919 (2007).
179. Gunji T, Matsuhashi N, Sato H et al Light and moderate alcohol consumption significantly reduces the prevalence of fatty liver in the japanese male population. Am. J. Gastroenterol. 104, 2189-2195 (2009).
180. Cotrim HP, Freitas LA, Alves E, Almeida A, May DS, Caldwell S. Effects of light-to-moderate alcohol consumption on steatosis and steatohepatitis in severely obese patients. Eur. J. Gastroenterol. Hepatol. 21 (9), 969-972 (2009). Low-moderate alcohol consumption may protect from insulin resistance in morbid obesity without exerting any deleterious effect on liver histology.
181. Hsieh SD, Yoshinaga H, Muto T, Sakurai Y Regular physical activity and coronary risk factors in Japanese men. Circulation 97, 661-665 (1998).
182. Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 130, 2023-2030 (2006).
183. Johnson NA, Sachinwalla T, Walton DW et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 50, 1105-1112 (2009).
184. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J. Hepatol. 49, 600-607 (2008).
185. Dunn W, Xu R, Wingard DL et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am. J. Gastroenterol. 103, 2263-2271 (2008).
186. Caldwell S, Lazo M. Is exercise an effective treatment for NASH? Knowns and unknowns. Annals of Hepatology 8 (Suppl.), S60-S66 (2009).
187. Harrison BC, Leinwand LA. Fighting fat with muscle: bulking up to slim down. Cell. Metab. 7, 97-98 (2008).
188. Izumiya Y, Hopkins T, Morris C et al. Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell. Metab. 7, 159-172 (2008).
189. Francaux M. Toll-like receptor signalling induced by endurance exercise Appl Physiol. Nutr. Metab. 34, 454-458 (2009). Toll-like receptors (TLRs) activation by non-esterified fatty acids may participate in the development of insulin resistance. Exercise seems to induce a down regulation of TLR expression in various tissues, a mechanism that may take part in the protective effect of exercise against insulin resistance.
190. Rector RS, Thyfault JP, Laye MJ et al Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. J. Physiol. 586 (Pt 17), 4241-4249 (2008).
191. Mortensen OH, Plomgaard P, Fischer CP, Hansen AK, Pilegaard H, Pedersen BK. PGC-1β is downregulated by training in human skeletal muscle: no effect of training twice every second day vs. once daily on expression of the PGC-1 family J. Appl. Physiol. 103, 1536-1542 (2007).
192. Farrell GC, Chitturi S, Lau GK, Sollano JD; Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary. J. Gastroenterol. Hepatol. 22, 775-777 (2007).
193. Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 134, 1682-1698 (2008).
194. Oh MK, Winn J, Poordad F. Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 28, 503-522 (2008).
195. Khashab M, Chalasani N. Use of insulin sensitizers in NASH. Endocrinol. Metab. Clin. North Am. 36, 1067-1087 (2007).
196. Orchard TJ, Temprosa M, Goldberg R; Diabetes Prevention Program Research group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann. Intern. Med. 142, 611-619 (2005).
197. Takano H, Hasegawa H, Zou Y, Komuro I. Pleiotropic actions of PPAR γ activators thiazolidinediones in cardiovascular diseases. Curr. Pharm. Des. 10, 2779-2786 (2004).
198. Halabi CM, Beyer AM, de Lange WJ et al Interference with PPAR γ function in smooth muscle causes vascular dysfunction and hypertension. Cell. Metab. 7, 215-226 (2008).
199. Heilbronn LK, Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr. Pharm. Des. 14, 1225-1230 (2008).
200. Ratziu V, Giral P, Jacqueminet S et al LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebocontrolled fatty liver improvement with rosiglitazone therapy (FLIRT) Trial. Gastroenterology 135, 100-110 (2008). In this randomized trial, rosiglitazone improved steatosis and transaminase levels despite weight gain, an effect related to an improvement in insulin sensitivity. However, there was no improvement in other parameters of liver injury.
201. Belfort R, Harrison SA, Brown K et al. NA placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl. J. Med. 355, 2297-2307 (2006). In this proof-of-concept study, the administration of pioglitazone for 6 months led to metabolic and histologic improvement in 55 subjects with NASH associated with impaired glucose tolerance or Type 2 diabetes.
202. Argo CK, Iezzoni JC, Al-Osaimi AM, Caldwell SH. Thiazolidinediones for the treatment in NASH: sustained benefit after drug discontinuation? J. Clin. Gastroenterol. 43, 565-568 (2009).
203. Argo CK, Loria P, Caldwell SH, Lonardo A. Statins in liver disease: a molehill, an iceberg, or neither? Hepatology 48, 662-669 (2008). In-depth review of all basic and clinical aspects of the interaction of liver and statins.
204. Greenfield V, Cheung O, Sanyal AJ. Recent advances in nonalcholic fatty liver disease. Curr. Opin. Gastroenterol. 24, 320-327 (2008).
205. Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin. Sci. (Lond). 115, 141-150 (2008).
206. Remick J, Weintraub H, Setton R, Offenbacher J, Fisher E, Schwartzbard A. Fibrate therapy: an update. Cardiol. Rev. 16, 129-141 (2008).
207. Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. EMBO J. 25, 1419-1425 (2006).
208. Wei J, Qiu de K, Ma X. Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver disease. J. Dig. Dis. 10, 85-90 (2009).
209. Herrema H, Meissner M, van Dijk TH et al. Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptora-controlled metabolic pathways in mice. Hepatology 51 (3), 806-816 (2009).
210. 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. 51, 771-784, (2010).
211. Orlando R, Azzalini L, Orando S, Lirussi F. Bile acids for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst. Rev. CD005160 (2007).
212. Bortolotti M, Kreis R, Debard C et al. High protein intake reduces intrahepatocellular lipid deposition in humans. Am. J. Clin. Nutr. 90, 1002-1010 (2009).
213. Yokohama S, Yoneda M, Haneda M et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 40, 1222-1225 (2004).
214. Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J. Gastrointestin. Liver Dis. 16, 39-46 (2007).
215. Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensinreceptor blockers as therapy for mild-tomoderate hypertension- associated non-alcoholic steatohepatitis. World J. Gastroenterol. 15, 942-954 (2009).
216. Inoue T, Node K. Telmisartan as a metabolic sartan for targeting vascular failure. Expert Opin. Pharmacother. 9, 1397-1406 (2008).
217. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am. J. Gastroenterol. 98, 2485-2490 (2003).
218. Yoneda M, Hasegawa T, Nakamura K, Tamano M, Kono T, Terano A. Vitamin E therapy in patients with NASH. Hepatology 40, 1222-1225 (2004).
219. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142, 37-46 (2005).
220. Misra P. AMP activated protein kinase: a next generation target for total metabolic control. Expert Opin. Ther Targets 12, 91-100 (2008).
221. Opie LH, Lecour S. The red wine hypothesis: from concepts to protective signalling molecules. Eur. Heart J. 28, 1683-1693 (2007).
222. Cucciolla V, Borriello A, Oliva A, Galletti P, Zappia V, Della Ragione F. Resveratrol: from basic science to the clinic. Cell Cycle 6, 2495-2510 (2007).
223. Markus MA, Morris BJ. Resveratrol in prevention and treatment of common clinical conditions of aging. Clin. Interv. Aging 3, 331-339 (2008).
224. Shankar S, Singh G, Srivastava RK. Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci. 12, 4839-4854 (2007).
225. Ahn J, Cho I, Kim S, Kwon D, Ha T. Dietary resveratrol alters lipid metabolismrelated gene expression of mice on an atherogenic diet. J. Hepatol. 49, 1019-1028 (2008).
226. Bujanda L, Hijona E, Larzabal M et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol. 8, 40 (2008).
227. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl Acad. Sci. USA 105, 9793-9798 (2008).
228. Feige JN, Lagouge M, Canto C et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell. Metab. 8, 347-358 (2008).
229. Morton NM, Seckl JR. 11β-hydroxysteroid dehydrogenase type 1 and obesity. Front Horm. Res. 36, 146-164 (2008).
230. Klein S, Fontana L, Young VL et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N. Engl. J. Med. 350, 2549-2557 (2004).
231. Mohammed BS, Cohen S, Reeds D, Young VL, Klein S. Long-term effects of large-volume liposuction on metabolic risk factors for coronary heart disease. Obesity (Silver Spring) 16, 2648-2651 (2008).
232. Giese SY, Bulan EJ, Commons GW, Spear SL, Yanovski JA. Improvements in cardiovascular risk profile with largevolume liposuction: a pilot study. Plast. Reconstr. Surg. 108, 510-519 (2001).
233. González-Ortiz M, Robles-Cervantes JA, Cárdenas-Camarena L, Bustos-Saldaña R, Martínez-Abundis E. The effects of surgically removing subcutaneous fat on the metabolic profile and insulin sensitivity in obese women after large-volume liposuction treatment. Horm. Metab. Res. 34, 446-449 (2002).
234. Robles-Cervantes JA, Yánez-Díaz S, Cárdenas-Camarena L. Modification of insulin, glucose and cholesterol levels in nonobese women undergoing liposuction: is liposuction metabolically safe? Ann. Plast. Surg. 52, 64-67 (2004).
235. D'Andrea F, Grella R, Rizzo MR et al. Changing the metabolic profile by large-volume liposuction: a clinical study conducted with 123 obese women. Aesthetic Plast. Surg. 29, 472-478, 481 (2005).
236. Rizzo MR, Paolisso G, Grella R et al. Is dermolipectomy effective in improving insulin action and lowering inflammatory markers in obese women? Clin. Endocrinol. (Oxf.) 63, 253-258 (2005).
237. Hong YG, Kim HT, Seo SW, Chang CH, Rhee EJ, Lee WY. Impact of large-volume liposuction on serum lipids in orientals: a pilot study. Aesthetic Plast. Surg. 30, 327-332 (2006).
238. Busetto L, Bassetto F, Zocchi M et al. The effects of the surgical removal of subcutaneous adipose tissue on energy expenditure and adipocytokine concentrations in obese women. Nutr. Metab Cardiovasc Dis. 18, 112-120 (2008).
239. Ybarra J, Blanco-Vaca F, Fernández S et al. The effects of liposuction removal of subcutaneous abdominal fat on lipid metabolism are independent of insulin sensitivity in normal-overweight individuals. Obes. Surg. 18, 408-414 (2008).
240. Seale P, Lazar MA. Brown fat in humans: turning up the heat on obesity. Diabetes 58, 1482-1484 (2009).
241. Cortez-Pinto H, Machado MV. Uncoupling proteins and non-alcoholic fatty liver disease. J. Hepatol. 50, 857-860 (2009).
242. Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43, 173-181 (2006).
243. Gary-Bobo M, Elachouri G, Gallas JF et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 46, 122-129 (2007).
244. Serrano A, Del Arco I, Javier Pavón F et al. The cannabinoid CB1 receptor antagonist SR141716A (Rimonabant) enhances the metabolic benefits of long-term treatment with oleoylethanolamide in Zucker rats. Neuropharmacology 54, 226-234 (2008).
245. Hill MN, Gorzalka BB. Impairments in endocannabinoid signaling and depressive illness. JAMA 301, 1165-1166 (2009).
246. Moreira FA, Grieb M, Lutz B. Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract. Res. Clin. Endocrinol. Metab. 23, 133-144 (2009).
247. Nair S, Cope K, Risby TH, Diehl AM. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 1200-1204 (2001) ;
248. Erratum in: Am. J. Gastroenterol. 96, 2809 (2001).
249. Bergheim I, Weber S, Vos M et al. Antibiotics protect against fructoseinduced hepatic lipid accumulation in mice: role of endotoxin. J. Hepatol. 48, 983-992 (2008).
250. Loguercio C, De Simone T, Federico A et al. Gut-liver axis: a new point of attack to treat chronic liver damage? Am. J. Gastroenterol. 97, 2144-2146 (2002).
251. American Gastroenterological Association. American Gastroenterological Association medical position statement on Obesity. Gastroenterology 123, 879-881 (2002).
252. Dixon JB, O'Brien PE, Playfair J et al. Adjustable gastric banding and conventional therapy for Type 2 diabetes: a randomized controlled trial. JAMA 299, 316-323 (2008).
253. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and metaanalysis. Clin. Gastroenterol. Hepatol. 6, 1396-1402 (2008).
254. Dongiovanni P, Valenti L, Rametta R et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 59, 267-273 (2010).