Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease

Nutrients - Tập 5 Số 5 - Trang 1544-1560
Melania Gaggini1, Mariangela Morelli1, E. Buzzigoli1, Ralph A. DeFronzo2, Elisabetta Bugianesi3, Amalia Gastaldelli2,1
1Institute of Clinical Physiology National Research Council, Pisa 56100, Italy
2Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78229, USA
3Department of Medical Sciences, Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, Turin 10126, Italy

Tóm tắt

Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.

Từ khóa


Tài liệu tham khảo

Szczepaniak, 1999, Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo, Am. J. Physiol., 276, E977

Browning, 2004, Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity, Hepatology, 40, 1387, 10.1002/hep.20466

Day, 2002, Pathogenesis of steatohepatitis, Best Pract. Res. Clin. Gastroenterol., 16, 663, 10.1053/bega.2002.0333

Chalasani, 2012, The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology, Gastroenterology, 142, 1592, 10.1053/j.gastro.2012.04.001

Fracanzani, 2008, Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes, Hepatology, 48, 792, 10.1002/hep.22429

Kotronen, 2008, Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects, Diabetes Care, 31, 165, 10.2337/dc07-1463

Gastaldelli, 2007, Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects, Gastroenterology, 133, 496, 10.1053/j.gastro.2007.04.068

Bellentani, 2000, Prevalence of and risk factors for hepatic steatosis in Northern Italy, Ann. Intern. Med., 132, 112, 10.7326/0003-4819-132-2-200001180-00004

Bhatia, 2012, Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?, Eur. Heart J., 33, 1190, 10.1093/eurheartj/ehr453

Sanyal, 2001, Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities, Gastroenterology, 120, 1183, 10.1053/gast.2001.23256

2010, Liver fat in the pathogenesis of insulin resistance and type 2 diabetes, Dig. Dis., 28, 203, 10.1159/000282087

Fabbrini, 2009, Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity, Proc. Natl. Acad. Sci. USA, 106, 15430, 10.1073/pnas.0904944106

Bugianesi, 2005, Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms, Diabetologia, 48, 634, 10.1007/s00125-005-1682-x

Kantartzis, 2009, Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene, Diabetes, 58, 2616, 10.2337/db09-0279

Sevastianova, 2011, Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans, Am. J. Clin. Nutr., 94, 104, 10.3945/ajcn.111.012369

Amaro, 2010, Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia, Gastroenterology, 139, 149, 10.1053/j.gastro.2010.03.039

Visser, 2011, Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia, Diabetologia, 54, 2113, 10.1007/s00125-011-2157-x

Kantartzis, 2009, The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans, Clin. Sci. (Lond.), 116, 531, 10.1042/CS20080306

Monetti, 2007, Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver, Cell Metab., 6, 69, 10.1016/j.cmet.2007.05.005

Targher, 2007, Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients, Diabetes Care, 30, 1212, 10.2337/dc06-2247

Lomonaco, 2012, Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease, Hepatology, 55, 1389, 10.1002/hep.25539

Arner, 2002, Insulin resistance in type 2 diabetes: Role of fatty acids, Diabetes Metab. Res. Rev., 18, S5, 10.1002/dmrr.254

Korenblat, 2008, Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects, Gastroenterology, 134, 1369, 10.1053/j.gastro.2008.01.075

Gastaldelli, 2009, Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis, Hepatology, 50, 1087, 10.1002/hep.23116

Fabbrini, 2008, Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease, Gastroenterology, 134, 424, 10.1053/j.gastro.2007.11.038

Adiels, 2006, Overproduction of large VLDL particles is driven by increased liver fat content in man, Diabetologia, 49, 755, 10.1007/s00125-005-0125-z

Miles, 2007, Contribution of triglyceride-rich lipoproteins to plasma free fatty acids, Horm. Metab. Res., 39, 726, 10.1055/s-2007-990273

Machado, 2012, Liver and muscle in morbid obesity: The interplay of fatty liver and insulin resistance, PLoS One, 7, e31738, 10.1371/journal.pone.0031738

Hwang, 2007, Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies, Am. J. Physiol. Endocrinol. Metab., 293, E1663, 10.1152/ajpendo.00590.2006

Choi, 2008, Hepatic triglyceride synthesis and nonalcoholic fatty liver disease, Curr. Opin. Lipidol., 19, 295, 10.1097/MOL.0b013e3282ff5e55

2010, Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of NASH, Curr. Gastroenterol. Rep., 12, 49, 10.1007/s11894-009-0083-6

Heni, 2010, Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: A nuclear magnetic resonance study, Diabetes Metab. Res. Rev., 26, 200, 10.1002/dmrr.1073

Kotronen, 2011, Comparison of the relative contributions of intra-abdominal and liver fat to components of the metabolic syndrome, Obesity (Silver Spring), 19, 23, 10.1038/oby.2010.137

Wald, 2012, Automatic quantification of subcutaneous and visceral adipose tissue from whole-body magnetic resonance images suitable for large cohort studies, J. Magn. Reson. Imaging, 36, 1421, 10.1002/jmri.23775

Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes, Gastroenterology, 135, 122, 10.1053/j.gastro.2008.03.021

Gastaldelli, 2011, Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus, Diabetes Res. Clin. Pract., 93, S60, 10.1016/S0168-8227(11)70015-8

Fabbrini, 2010, Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults, Gastroenterology, 139, 448, 10.1053/j.gastro.2010.04.056

Albu, 1999, Systemic resistance to the antilipolytic effect of insulin in black and white women with visceral obesity, Am. J. Physiol., 277, E551

Wajchenberg, 2000, Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome, Endocr. Rev., 21, 697, 10.1210/edrv.21.6.0415

Jensen, 2008, Role of body fat distribution and the metabolic complications of obesity, J. Clin. Endocrinol. Metab., 93, S57, 10.1210/jc.2008-1585

Moore, 1998, Autoregulation of hepatic glucose production, Eur. J. Endocrinol., 138, 240, 10.1530/eje.0.1380240

Gastaldelli, 2000, Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study, Diabetes, 49, 1367, 10.2337/diabetes.49.8.1367

Jenssen, 1990, Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration, J. Clin. Invest., 86, 489, 10.1172/JCI114735

Gastaldelli, 2009, Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population, Hepatology, 49, 1537, 10.1002/hep.22845

Sunny, 2011, Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease, Cell Metab., 14, 804, 10.1016/j.cmet.2011.11.004

Gastaldelli, 2002, Metabolic effects of visceral fat accumulation in type 2 diabetes, J. Clin. Endocrinol. Metab., 87, 5098, 10.1210/jc.2002-020696

Boden, 2001, Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes, Diabetes, 50, 810, 10.2337/diabetes.50.4.810

Wajngot, 2001, Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus, Metabolism, 50, 47, 10.1053/meta.2001.19422

Souza, 2012, Metabolic syndrome and risk factors for non-alcoholic fatty liver disease, Arq. Gastroenterol., 49, 89, 10.1590/S0004-28032012000100015

Barrows, 2005, Spillover of dietary fatty acids and use of serum nonesterified fatty acids for the synthesis of VLDL-triacylglycerol under two different feeding regimens, Diabetes, 54, 2668, 10.2337/diabetes.54.9.2668

Chapman, 2011, Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management, Eur. Heart J., 32, 1345, 10.1093/eurheartj/ehr112

Bugianesi, 2005, 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, 10.1210/jc.2004-2240

Gastaldelli, 2010, Pioglitazone in the treatment of NASH: the role of adiponectin, Aliment. Pharmacol. Ther., 32, 769, 10.1111/j.1365-2036.2010.04405.x

Yamauchi, 2002, Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase, Nat. Med., 8, 1288, 10.1038/nm788

Marchesini, 2001, Nonalcoholic fatty liver disease: A feature of the metabolic syndrome, Diabetes, 50, 1844, 10.2337/diabetes.50.8.1844

Aygun, 2007, Evaluation of metabolic syndrome frequency and carotid artery intima-media thickness as risk factors for atherosclerosis in patients with nonalcoholic fatty liver disease, Dig. Dis. Sci., 53, 1352, 10.1007/s10620-007-9998-7

Marchesini, 2003, Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome, Hepatology, 37, 917, 10.1053/jhep.2003.50161

Kantartzis, 2008, Fatty liver is independently associated with alterations in circulating HDL2 and HDL3 subfractions, Diabetes Care, 31, 366, 10.2337/dc07-1558

Toledo, 2006, Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes, Diabetes Care, 29, 1845, 10.2337/dc06-0455

Sung, 2012, Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people, Diabetes Care, 35, 2359, 10.2337/dc12-0515

Vanni, 2010, From the metabolic syndrome to NAFLD or vice versa?, Dig. Liver Dis., 42, 320, 10.1016/j.dld.2010.01.016

Gastaldelli, 2010, Fatty liver disease: the hepatic manifestation of metabolic syndrome, Hypertens. Res., 33, 546, 10.1038/hr.2010.60

Ribeireiro, 2011, NAFLD and insulin resistance do not increase the risk of postoperative complications among patients undergoing bariatric surgery––A prospective analysis, Obes. Surg., 21, 310, 10.1007/s11695-010-0228-6

Huang, 2007, Metabolic syndrome is related to nonalcoholic steatohepatitis in severely obese subjects, Obes. Surg., 17, 1457, 10.1007/s11695-008-9423-0

Sironi, 2011, Ectopic fat storage, insulin resistance, and hypertension, Curr. Pharm. Des., 17, 3074, 10.2174/138161211798157720

Gastaldelli, 2010, Ectopic fat and cardiovascular disease: What is the link?, Nutr. Metab. Cardiovasc. Dis., 20, 481, 10.1016/j.numecd.2010.05.005

Ghouri, 2010, Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: A narrative review and clinical perspective of prospective data, Hepatology, 52, 1156, 10.1002/hep.23789

Lomonaco, 2012, Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD), Diabetes Care, 35, 873, 10.2337/dc11-1849

Targher, 2011, Risk of all-cause and cardiovascular mortality in patients with chronic liver disease, Gut, 60, 1602, 10.1136/gut.2010.230656

Targher, 2006, Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease, Diabet. Med., 23, 403, 10.1111/j.1464-5491.2006.01817.x

2005, Fat in the liver and insulin resistance, Ann. Med., 37, 347, 10.1080/07853890510037383

Auberger, 1989, Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity, Cell, 58, 631, 10.1016/0092-8674(89)90098-6

Pal, 2012, Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance, Nat. Med., 18, 1279, 10.1038/nm.2851

Hennige, 2008, Fetuin-A induces cytokine expression and suppresses adiponectin production, PLoS One, 3, e1765, 10.1371/journal.pone.0001765

Dogru, 2013, Plasma fetuin-A is associated with endothelial dysfunction and subclinical atherosclerosis in subjects with nonalcoholic fatty liver disease, Clin. Endocrinol. (Oxf.), 78, 712, 10.1111/j.1365-2265.2012.04460.x

Rittig, 2009, High plasma fetuin-A is associated with increased carotid intima-media thickness in a middle-aged population, Atherosclerosis, 207, 341, 10.1016/j.atherosclerosis.2009.05.018

Weikert, 2008, Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke, Circulation, 118, 2555, 10.1161/CIRCULATIONAHA.108.814418

Stefan, 2008, Plasma fetuin-A levels and the risk of type 2 diabetes, Diabetes, 57, 2762, 10.2337/db08-0538

Villanova, 2005, Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease, Hepatology, 42, 473, 10.1002/hep.20781

Kozakova, 2012, Fatty liver index, gamma-glutamyltransferase, and early carotid plaques, Hepatology, 55, 1406, 10.1002/hep.25555

Bonapace, 2012, Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes, Diabetes Care, 35, 389, 10.2337/dc11-1820

Mofrad, 2003, Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values, Hepatology, 37, 1286, 10.1053/jhep.2003.50229

Ricci, 1997, Noninvasive in vivo quantitative assessment of fat content in human liver, J. Hepatol., 27, 108, 10.1016/S0168-8278(97)80288-7

Tsuneto, 2010, Fatty liver incidence and predictive variables, Hypertens. Res., 33, 638, 10.1038/hr.2010.45

Bedogni, 2006, The Fatty Liver Index: A simple and accurate predictor of hepatic steatosis in the general population, BMC Gastroenterol., 6, 33, 10.1186/1471-230X-6-33

Targher, 2010, Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease, N. Engl. J. Med., 363, 1341, 10.1056/NEJMra0912063

Hill, 2003, Circulating endothelial progenitor cells, vascular function, and cardiovascular risk, N. Engl. J. Med., 348, 593, 10.1056/NEJMoa022287

Chiang, 2012, Decreased circulating endothelial progenitor cell levels and function in patients with nonalcoholic fatty liver disease, PLoS One, 7, e31799, 10.1371/journal.pone.0031799

Lin, 2005, Sonographic fatty liver, overweight and ischemic heart disease, World J. Gastroenterol., 11, 4838, 10.3748/wjg.v11.i31.4838

Bugianesi, 2012, Hepatic and cardiac steatosis: Are they coupled?, Heart Fail. Clin., 8, 663, 10.1016/j.hfc.2012.06.010

Assy, 2010, Presence of coronary plaques in patients with nonalcoholic fatty liver disease, Radiology, 254, 393, 10.1148/radiol.09090769

Ebrahimi, 2009, Metabolic syndrome may not be a good predictor of coronary artery disease in the Iranian population: population-specific definitions are required, Sci. World J., 9, 86, 10.1100/tsw.2009.17