The role of visceral adipose tissue in the pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease in Western countries, comprises a disease spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. Fatty liver develops when fatty acid uptake and de novo fatty acid synthesis exceed fatty acid oxidation and export as very low-density lipoprotein/triglycerides. Because of its high prevalence and its association with obesity, metabolic syndrome, type 2 diabetes, dyslipidaemia and hypertension, NAFLD has become an important public health problem. The pathogenesis of NAFLD has to date not been completely clarified. Research has been conducted regarding the role of insulin resistance, lipotoxicity, oxidative stress and chronic inflammation. Visceral adipose tissue has increasingly been recognised as a biologically active organ contributing to the pathogenesis of NAFLD. Its role in the development of fatty liver might be situated at several levels: as a source of free fatty acids, by the production of adipocytokines, as a cause of insulin resistance and by inflammation.

[1]  G. Hubens,et al.  Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension , 2011, International Journal of Obesity.

[2]  William O Richards,et al.  Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. , 2010, Gastroenterology.

[3]  G. Musso,et al.  A meta‐analysis of randomized trials for the treatment of nonalcoholic fatty liver disease , 2010, Hepatology.

[4]  M. Stumvoll,et al.  Retinol-binding protein 4 and new adipocytokines in nonalcoholic fatty liver disease. , 2010, Current pharmaceutical design.

[5]  G. Svegliati-Baroni,et al.  From the metabolic syndrome to NAFLD or vice versa? , 2010, Digestive and Liver Disease.

[6]  C. Day Genetic and Environmental Susceptibility to Non-Alcoholic Fatty Liver Disease , 2010, Digestive Diseases.

[7]  I. Lemieux,et al.  Obesity, Inflammation, and Cardiovascular Risk , 2010, Clinical pharmacology and therapeutics.

[8]  G. Steinberg,et al.  Adipose tissue as an endocrine organ , 2010, Molecular and Cellular Endocrinology.

[9]  R. Margis,et al.  SIRT1 Transcription Is Decreased in Visceral Adipose Tissue of Morbidly Obese Patients with Severe Hepatic Steatosis , 2010, Obesity surgery.

[10]  E. van Marck,et al.  Non‐alcoholic steatohepatitis induces non‐fibrosis‐related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model , 2010, Liver international : official journal of the International Association for the Study of the Liver.

[11]  B. Neuschwander‐Tetri Nontriglyceride Hepatic Lipotoxicity: The New Paradigm for the Pathogenesis of NASH , 2010, Current gastroenterology reports.

[12]  L. Gaal,et al.  Visceral adipose tissue and inflammation correlate with elevated liver tests in a cohort of overweight and obese patients , 2010, International Journal of Obesity.

[13]  S. Klein,et al.  Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications , 2010, Hepatology.

[14]  M. Blüher The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals , 2010, Current opinion in lipidology.

[15]  P. Giral,et al.  Long‐term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial , 2009, Hepatology.

[16]  B. Vergès,et al.  CB1 Antagonism Exerts Specific Molecular Effects on Visceral and Subcutaneous Fat and Reverses Liver Steatosis in Diet-Induced Obese Mice , 2010, Diabetes.

[17]  E. Brunt,et al.  Nonalcoholic fatty liver disease: pathology and pathogenesis. , 2010, Annual review of pathology.

[18]  G. Musso,et al.  Non‐alcoholic fatty liver disease from pathogenesis to management: an update , 2009, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[19]  F. Marra,et al.  Adipokines in liver diseases , 2009, Hepatology.

[20]  A. Sanyal,et al.  Recent advances in nonalcoholic fatty liver disease , 2009, Current opinion in gastroenterology.

[21]  M. Blüher,et al.  Adipose tissue dysfunction in obesity. , 2009, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[22]  M. Vázquez-Carrera,et al.  Suppressor of cytokine signaling‐3 (SOCS‐3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism , 2008, Hepatology.

[23]  U. Broedl,et al.  Adipokines and Insulin Resistance , 2008, Molecular medicine.

[24]  J. Olefsky,et al.  Insulin sensitivity: modulation by nutrients and inflammation. , 2008, The Journal of clinical investigation.

[25]  G. Marsicano,et al.  Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. , 2008, The Journal of clinical investigation.

[26]  Dympna Gallagher,et al.  Assessment methods in human body composition , 2008, Current opinion in clinical nutrition and metabolic care.

[27]  J. Kench,et al.  Visceral fat: A key mediator of steatohepatitis in metabolic liver disease , 2008, Hepatology.

[28]  Philippe Giral,et al.  Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. , 2008, Gastroenterology.

[29]  A. Kotronen,et al.  Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. , 2008, Gastroenterology.

[30]  Ja-june Jang,et al.  Visceral adipose tissue area is an independent risk factor for hepatic steatosis , 2008, Journal of gastroenterology and hepatology.

[31]  J. Mancero,et al.  Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[32]  N. Stefan,et al.  Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production , 2008, PloS one.

[33]  J. Delgado Evolving trends in nonalcoholic fatty liver disease. , 2008, European journal of internal medicine.

[34]  Heike Münzberg,et al.  Mechanisms of leptin action and leptin resistance. , 2008, Annual review of physiology.

[35]  B. S. Mohammed,et al.  Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. , 2008, Gastroenterology.

[36]  A. Kotronen,et al.  Effect of liver fat on insulin clearance. , 2007, American journal of physiology. Endocrinology and metabolism.

[37]  M. Duvnjak,et al.  Pathogenesis and management issues for non-alcoholic fatty liver disease. , 2007, World journal of gastroenterology.

[38]  G. Shulman,et al.  Obesity-associated improvements in metabolic profile through expansion of adipose tissue. , 2007, The Journal of clinical investigation.

[39]  C. Mantzoros,et al.  High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice* , 2007, Journal of Biological Chemistry.

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

[41]  P. Soubrié,et al.  Rimonabant reduces obesity‐associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats , 2007, Hepatology.

[42]  J. Després,et al.  Cardiovascular disease under the influence of excess visceral fat. , 2007, Critical pathways in cardiology.

[43]  Zhenqi Liu,et al.  Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver)? , 2007, Journal of gastroenterology and hepatology.

[44]  A. Hamsten,et al.  Increased expression of the macrophage markers and of 11β-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity , 2007, International Journal of Obesity.

[45]  A. Halpern,et al.  Effects of bariatric surgery on nonalcoholic fatty liver disease: Preliminary findings after 2 years , 2007, Journal of gastroenterology and hepatology.

[46]  N. Assy,et al.  Weight loss induced by orlistat reverses fatty infiltration and improves hepatic fibrosis in obese patients with non-alcoholic steatohepatitis , 2007, Gut.

[47]  Y. Terauchi,et al.  Hypoadiponectinemia plays a crucial role in the development of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus independent of visceral adipose tissue. , 2007, Alcoholism, clinical and experimental research.

[48]  E. Bugianesi,et al.  Non-alcoholic steatohepatitis and cancer. , 2007, Clinics in liver disease.

[49]  S. Majumdar,et al.  Drug treatments for obesity: orlistat, sibutramine, and rimonabant , 2007, The Lancet.

[50]  C. Block,et al.  Mechanisms linking obesity with cardiovascular disease , 2006, Nature.

[51]  I. Lemieux,et al.  Abdominal obesity and metabolic syndrome , 2006, Nature.

[52]  J. Hardies,et al.  A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. , 2006, The New England journal of medicine.

[53]  C. Day,et al.  Genes or environment to determine alcoholic liver disease and non‐alcoholic fatty liver disease , 2006, Liver international : official journal of the International Association for the Study of the Liver.

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

[55]  J. Dixon,et al.  Weight Loss and Non-alcoholic Fatty Liver Disease: Falls In Gamma-Glutamyl Transferase Concentrations are Associated with Histologic Improvement , 2006, Obesity surgery.

[56]  N. Luciani,et al.  The Inflammatory C-Reactive Protein is Increased in Both Liver and Adipose Tissue in Severely Obese Patients Independently from Metabolic Syndrome, Type 2 Diabetes, and NASH , 2006, The American Journal of Gastroenterology.

[57]  B. Viollet,et al.  Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. , 2006, Endocrinology.

[58]  A. Csendes,et al.  Histological Findings in the Liver Before and After Gastric Bypass , 2006, Obesity surgery.

[59]  Yoichiro Kitajima,et al.  Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease , 2006, Journal of Gastroenterology.

[60]  M. Leshno,et al.  Double-Blind Randomized Placebo-Controlled Trial of Orlistat or the Treatment of Nonalcoholic Fatty Liver Disease , 2022 .

[61]  D. Brenner,et al.  Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. , 2006, Gastroenterology.

[62]  I. Goldberg,et al.  Ins and outs modulating hepatic triglyceride and development of nonalcoholic fatty liver disease. , 2006, Gastroenterology.

[63]  A. Xu,et al.  Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. , 2006, Biochemical and biophysical research communications.

[64]  E. Shaffer Bariatric surgery: a promising solution for nonalcoholic steatohepatitis in the very obese. , 2006, Journal of clinical gastroenterology.

[65]  A. Häkkinen,et al.  Overproduction of large VLDL particles is driven by increased liver fat content in man , 2006, Diabetologia.

[66]  A. Greenberg,et al.  Obesity and the role of adipose tissue in inflammation and metabolism. , 2006, The American journal of clinical nutrition.

[67]  R. Ross,et al.  Visceral Fat Is an Independent Predictor of All‐cause Mortality in Men , 2006, Obesity.

[68]  C. Rattarasarn Physiological and pathophysiological regulation of regional adipose tissue in the development of insulin resistance and type 2 diabetes , 2006, Acta physiologica.

[69]  S. Harrison,et al.  Non-Alcoholic Steatohepatitis: Effect of Roux-en-Y Gastric Bypass Surgery , 2006, The American Journal of Gastroenterology.

[70]  M. Fishbein,et al.  Relationship of Hepatic Steatosis to Adipose Tissue Distribution in Pediatric Nonalcoholic Fatty Liver Disease , 2006, Journal of pediatric gastroenterology and nutrition.

[71]  J. Olefsky,et al.  Inflamed fat: what starts the fire? , 2005, The Journal of clinical investigation.

[72]  S. Grundy,et al.  The metabolic syndrome. , 2008, Endocrine reviews.

[73]  G. Marchesini,et al.  Insulin resistance: A metabolic pathway to chronic liver disease , 2005, Hepatology.

[74]  Shupei Wang,et al.  Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200 , 2005, Journal of Lipid Research.

[75]  G. Marchesini,et al.  Review article: the treatment of fatty liver disease associated with the metabolic syndrome , 2005, Alimentary pharmacology & therapeutics.

[76]  E. Brunt Nonalcoholic steatohepatitis: pathologic features and differential diagnosis. , 2005, Seminars in diagnostic pathology.

[77]  Paul Zimmet,et al.  The metabolic syndrome—a new worldwide definition , 2005, The Lancet.

[78]  E. Yeh,et al.  Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. , 2005, Journal of the American College of Cardiology.

[79]  E. Ford Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. , 2005, Diabetes care.

[80]  R. Yu,et al.  Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-α and IL-6 , 2005 .

[81]  K. Mackie,et al.  Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. , 2005, The Journal of clinical investigation.

[82]  J. Westerbacka,et al.  The fatty liver and insulin resistance. , 2005, Current molecular medicine.

[83]  A. Rissanen,et al.  Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study , 2005, The Lancet.

[84]  S. B. Pedersen,et al.  Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. , 2005, The Journal of clinical endocrinology and metabolism.

[85]  W. Markiewicz,et al.  Association Between Elevated Liver Enzymes and C-Reactive Protein: Possible Hepatic Contribution to Systemic Inflammation in the Metabolic Syndrome , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[86]  I. S. Wood,et al.  Adipokines: inflammation and the pleiotropic role of white adipose tissue , 2004, British Journal of Nutrition.

[87]  D. Helinski,et al.  A pilot study of orlistat treatment in obese, non‐alcoholic steatohepatitis patients , 2004, Alimentary pharmacology & therapeutics.

[88]  J. Everhart,et al.  Epidemiology of nonalcoholic fatty liver. , 2004, Clinics in liver disease.

[89]  Y. Saijo,et al.  Relationship between C‐reactive protein and visceral adipose tissue in healthy Japanese subjects , 2004, Diabetes, obesity & metabolism.

[90]  H. Kim,et al.  Insulin resistance and C‐reactive protein as independent risk factors for non‐alcoholic fatty liver disease in non‐obese Asian men , 2004, Journal of gastroenterology and hepatology.

[91]  P Christoffersen,et al.  Long term prognosis of fatty liver: risk of chronic liver disease and death , 2004, Gut.

[92]  J. Freudenheim,et al.  Body fat distribution, relative weight, and liver enzyme levels: A population‐based study , 2004, Hepatology.

[93]  S. R. Ferreira,et al.  Methods of estimation of visceral fat: advantages of ultrasonography. , 2003, Obesity research.

[94]  B. Neuschwander‐Tetri,et al.  Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR‐γ ligand rosiglitazone , 2003, Hepatology.

[95]  C. Flachskamm,et al.  The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. , 2003, The Journal of clinical investigation.

[96]  Yu Wang,et al.  The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. , 2003, The Journal of clinical investigation.

[97]  D. Loskutoff,et al.  Monocyte chemoattractant protein 1 in obesity and insulin resistance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[98]  P. Soubrié,et al.  The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. , 2003, Molecular pharmacology.

[99]  G. Marchesini,et al.  Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome , 2003, Hepatology.

[100]  Hitoshi Nishizawa,et al.  Reciprocal Association of C-Reactive Protein With Adiponectin in Blood Stream and Adipose Tissue , 2003, Circulation.

[101]  C. Day Pathogenesis of steatohepatitis. , 2002, Best practice & research. Clinical gastroenterology.

[102]  M. Matsuda,et al.  Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 , 2002, Nature Medicine.

[103]  Y. Takei,et al.  Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. , 2002, Gastroenterology.

[104]  G. Sergi,et al.  Liver volume and visceral obesity in women with hepatic steatosis undergoing gastric banding. , 2002, Obesity research.

[105]  F. Brancati,et al.  Nonalcoholic fatty liver disease. , 2002, Gastroenterology.

[106]  F. Lönnqvist,et al.  A pilot study of long-term effects of a novel obesity treatment: omentectomy in connection with adjustable gastric banding , 2002, International Journal of Obesity.

[107]  E. Muls,et al.  The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study , 2001, International Journal of Obesity.

[108]  N. Sattar,et al.  Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians , 2001, International Journal of Obesity.

[109]  G. Marchesini,et al.  Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. , 2001, Diabetes.

[110]  J. Després,et al.  Elevated C-Reactive Protein: Another Component of the Atherothrombotic Profile of Abdominal Obesity , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[111]  W. Ricart,et al.  Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. , 2001, The Journal of clinical endocrinology and metabolism.

[112]  B. Wajchenberg Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. , 2000, Endocrine reviews.

[113]  G. Shulman,et al.  On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance , 2022 .

[114]  M. Visser,et al.  Elevated C-reactive protein levels in overweight and obese adults. , 1999, JAMA.

[115]  E. Ford Body mass index, diabetes, and C-reactive protein among U.S. adults. , 1999, Diabetes care.

[116]  A. Rissanen,et al.  Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients , 1998, The Lancet.

[117]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[118]  A. Scheen,et al.  Liver abnormalities in severely obese subjects: Effect of drastic weight loss after gastroplasty , 1998, International Journal of Obesity.

[119]  K. Tanikawa,et al.  Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. , 1997, Journal of hepatology.

[120]  K. Petersen,et al.  Mechanism of free fatty acid-induced insulin resistance in humans. , 1996, The Journal of clinical investigation.

[121]  R M Peshock,et al.  Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers. , 1994, Journal of lipid research.

[122]  J. Wang,et al.  Body fat topography as an independent predictor of fatty liver. , 1993, Metabolism: clinical and experimental.

[123]  N Karstaedt,et al.  Adipose tissue determinations in cadavers--a comparison between cross-sectional planimetry and computed tomography. , 1990, International journal of obesity.

[124]  G. Reaven Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[125]  M. CORREA ITURRASPE [Surgical treatment of obesity]. , 1952, Revista de la Asociacion Medica Argentina.

[126]  G. G. Van den Eynden,et al.  Rapidly evolving liver decompensation with some remarkable features 14 years after biliopancreatic derivation: a case report and literature review. , 2010, Acta gastro-enterologica Belgica.

[127]  H. Bays "Sick fat," metabolic disease, and atherosclerosis. , 2009, The American journal of medicine.

[128]  K. Shiratori,et al.  Imaging of nonalcoholic steatohepatitis: advantages and pitfalls of ultrasonography and computed tomography. , 2009, Internal medicine.

[129]  S. Friedman Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. , 2008, Physiological reviews.

[130]  B. Richelsen,et al.  Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects , 2005, International Journal of Obesity.

[131]  R. Yu,et al.  Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. , 2005, Diabetes research and clinical practice.

[132]  L. Sjöström,et al.  XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. , 2004, Diabetes care.

[133]  J. Tuomilehto,et al.  Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. , 2004, Archives of internal medicine.

[134]  L. Scott,et al.  Orlistat , 2012, Drugs.

[135]  A. Rissanen,et al.  Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. , 1998, Lancet.

[136]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[137]  J. Kral,et al.  Surgical treatment of obesity. , 1989, The Medical clinics of North America.

[138]  F. Schaffner,et al.  Nonalcoholic fatty liver disease. , 1986, Progress in liver diseases.