비알코올성 지방간질환의 발병기전에 대한 최신지견
Recent update on pathogenesis of nonalcoholic fatty liver disease
2
조회
0
다운로드
11
인용
0
참고문헌
초록
Recently, the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in Korean population. NAFLD includes a spectrum of hepatic pathology from simple steatosis in its most benign form, to nonalcoholic steatohepatitis (NASH) and/or cirrhosis. NAFLD has a strong association with type 2 diabetes and obesity, and thus it is now recognized to represent the hepatic manifestation of metabolic syndrome. The pathogenesis of simple steatosis occurrence and its progression to NASH is not entirely elucidated and multi-factorial. Liver fat accumulation is mainly induced by insulin resistance and increased free fatty acids, and then NASH is developed by oxidative stress, lipid peroxidation, mitochondrial dysfunction, gut-derived endotoxin, and cytokine/adipokine interplay. Genetic factors and environmental factors such as exercise and high fat and high fructose diet also participate in the development of NAFLD. This review is focused to summarize the up-to-date understanding of NAFLD pathogenesis.
Abstract
Recently, the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in Korean population. NAFLD includes a spectrum of hepatic pathology from simple steatosis in its most benign form, to nonalcoholic steatohepatitis (NASH) and/or cirrhosis. NAFLD has a strong association with type 2 diabetes and obesity, and thus it is now recognized to represent the hepatic manifestation of metabolic syndrome. The pathogenesis of simple steatosis occurrence and its progression to NASH is not entirely elucidated and multi-factorial. Liver fat accumulation is mainly induced by insulin resistance and increased free fatty acids, and then NASH is developed by oxidative stress, lipid peroxidation, mitochondrial dysfunction, gut-derived endotoxin, and cytokine/adipokine interplay. Genetic factors and environmental factors such as exercise and high fat and high fructose diet also participate in the development of NAFLD. This review is focused to summarize the up-to-date understanding of NAFLD pathogenesis.
참고문헌 (103)
- Brunt EM, "Nonalcoholic steatohepatitis: definition and pathology", Semin Liver Dis, 21, pp.3~16 (2001)
- Browning JD, "Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity", Hepatology, 40, pp.1387~1395 (2004)
- Day CP, "Natural history of NAFLD: remarkably benign in the absence of cirrhosis", Gastroenterology, 129, pp.375~378 (2005)
- Ekstedt M, "Long-term follow-up of patients with NAFLD and elevated liver enzymes", Hepatology, 44, pp.865~873 (2006)
- Fassio E, "Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies", Hepatology, 40, pp.820~826 (2004)
- Adams LA, "The natural history of nonalcoholic fatty liver disease: a population-based cohort study", Gastroenterology, 129, pp.113~124 (2005)
- Matteoni CA, "Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity", Gastroenterology, 116, pp.1413~1419 (1999)
- Day CP, "Steatohepatitis: a tale of two “hits”?", Gastroenterology, 114, pp.842~845 (1998)
- Harrison SA, "Nonalcoholic steatohepatitis: what we know in the new millennium", Am J Gastroenterol, 97, pp.2714~2724 (2002)
- Yamaguchi K, "Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis", Hepatology, 45, pp.1366~1374 (2007)
- Feldstein AE, "Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway", Hepatology, 40, pp.185~194 (2004)
- Jou J, "Mechanisms of disease progression in nonalcoholic fatty liver disease", Semin Liver Dis, 28, pp.370~379 (2008)
- Gambino R, "Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH?", Hepatology, 45, pp.1097~1107 (2007)
- Musso G, "Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH", Hepatology, 47, pp.1167~1177 (2008)
- Namikawa C, "Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis", J Hepatol, 40, pp.781~786 (2004)
- Miele L, "The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease", Gastroenterology, 135, pp.282~291 (2008)
- Romeo S, "Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease", Nat Genet, 40, pp.1461~1465 (2008)
- Petersen KF, "Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease", N Engl J Med, 362, pp.1082~1089 (2010)
- Musso G, "Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis", Hepatology, 37, pp.909~916 (2003)
- Toshimitsu K, "Dietary habits and nutrient intake in non-alcoholic steatohepatitis", Nutrition, 23, pp.46~52 (2007)
- Bergheim I, "Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin", J Hepatol, 48, pp.983~992 (2008)
- Tetri LH, "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, pp.G987~G995 (2008)
- Suzuki A, "Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease", J Hepatol, 43, pp.1060~1066 (2005)
- Kechagias S, "Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects", Gut, 57, pp.649~654 (2008)
- Barrès R, "Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density", Cell Metab, 10, pp.189~198 (2009)
- Adams LA, "The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies", J Hepatol, 42, pp.132~138 (2005)
- Cheung O, "Abnormalities of lipid metabolism in nonalcoholic fatty liver disease", Semin Liver Dis, 28, pp.351~359 (2008)
- Donnelly KL, "Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease", J Clin Invest, 115, pp.1343~1351 (2005)
- Puri P, "A lipidomic analysis of nonalcoholic fatty liver disease", Hepatology, 46, pp.1081~1090 (2007)
- Musso G, "Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)", Prog Lipid Res, 48, pp.1~26 (2008)
- Evans RM, "PPARs and the complex journey to obesity", Nat Med, 10, pp.355~361 (2004)
- Bugianesi E, "Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma", Gastroenterology, 123, pp.134~140 (2002)
- Gavrilova O, "Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes", J Clin Invest, 111, pp.737~747 (2003)
- Horton JD, "SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver", J Clin Invest, 109, pp.1125~1131 (2002)
- Iizuka K, "Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis", Proc Natl Acad Sci U S A, 101, pp.7281~7286 (2004)
- Dentin R, "Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression", J Biol Chem, 279, pp.20314~20326 (2004)
- Dentin R, "Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob", ob mice, 2006, pp.55, 2159~2170
- Schreuder TC, "Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment", World J Gastroenterol, 14, pp.2474~2486 (2008)
- Semple RK, "PPAR gamma and human metabolic disease", J Clin Invest, 116, pp.581~589 (2006)
- Pfutzner A, "Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control", Horm Metab Res, 37, pp.510~515 (2005)
- Yu S, "Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression", J Biol Chem, 278, pp.498~505 (2003)
- Browning JD, "Molecular mediators of hepatic steatosis and liver injury", J Clin Invest, 114, pp.147~152 (2004)
- Larter CZ, "Insulin resistance, adiponectin, cytokines in NASH: which is the best target to treat?", J Hepatol, 44, pp.253~261 (2006)
- Mitro N, "The nuclear receptor LXR is a glucose sensor", Nature, 445, pp.219~223 (2007)
- Zhou J, "Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis", Gastroenterology, 134, pp.556~567 (2008)
- Denechaud PD, "Role of ChREBP in hepatic steatosis and insulin resistance", FEBS Lett, 582, pp.68~73 (2008)
- Ueki K, "Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms", Mol Cell Biol, 24, pp.5434~5446 (2004)
- Tendler D, "The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study", Dig Dis Sci, 52, pp.589~593 (2007)
- Ueno T, "Therapeutic effects of restrictra diet and exercise in obese patients with fatty liver", J Hepatol, pp.103~107 (1997)
- Curat CA, "Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin", Diabetologia, 49, pp.744~747 (2006)
- Wang Y, "Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans", Clin Chem, 53, pp.34~41 (2007)
- Petta S, "Non-alcoholic fatty liver disease pathogenesis: the present and the future", Dig Liver Dis, 41, pp.615~625 (2009)
- van der Poorten D, "Visceral fat: a key mediator of steatohepatitis in metabolic liver disease", Hepatology, 48, pp.449~457 (2008)
- Ronti T, "The endocrine function of adipose tissue: an update", Clin Endocrinol, 64, pp.355~365 (2006)
- Le Roith D, "Recent advances in our understanding of insulin action and insulin resistance", Diabetes Car, 24, pp.588~597 (2001)
- Ferré P, "SREBP-1c transcription factor and lipid homeostasis: clinical perspective", Horm Res, 68, pp.72~82 (2007)
- Park SH, "Nonalcoholic steatohepatitis: pathogenesis and treatment", Korean J Hepatol, 14, pp.12~27 (2008)
- Krebs DL, "SOCS: physiological suppressors of cytokine signaling", J Cell Sci, 113, pp.2813~2819 (2000)
- Kim JK, "Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance", Proc Natl Acad Sci USA, 98, pp.7522~7527 (2001)
- Sanyal AJ, "Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities", Gastroenterology, 120, pp.1183~1192 (2001)
- Paradis V, "High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis", Hepatology, 34, pp.738~744 (2001)
- Ozcan U, "Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes", Science, 306, pp.457~461 (2004)
- Svegliati-Baroni G, "Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways", Hepatology, 29, pp.1743~1751 (1999)
- Marchesini G, "Association of nonalcoholic fatty liver disease with insulin resistance", Am J Med, 107, pp.450~455 (1999)
- St-Pierre J, "Topology of superoxide production from different sites in the mitochondrial electron transport chain", J Biol Chem, 277, pp.44784~44790 (2002)
- Du XL, "Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation", Proc Natl Acad Sci U S A, 97, pp.12222~12226 (2000)
- Perez-Carreras M, "Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis", Hepatology, 38, pp.999~1007 (2003)
- Bilzer M, "Role of Kupffer cells in host defense and liver disease", Liver Int, 26, pp.1175~1186 (2006)
- Lefkowitch JH, "Kupffer cell aggregation and perivenular distribution in steatohepatitis", Mod Pathol, 15, pp.699~704 (2002)
- Huang H, "Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet", J Inflamm, 4, pp.22~ (2007)
- Li Z, "Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease", Hepatology, 37, pp.343~350 (2003)
- Ma X, "Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells", J Hepatol, 49, pp.821~830 (2008)
- Velayudham A, "VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice", Hepatology, 49, pp.989~997 (2009)
- Miura K, "Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice", Gastroenterology, 139, pp.323~334 (2010)
- Marra F, "Adipokines in liver diseases", Hepatology, 50, pp.957~969 (2009)
- Kadowaki T, "Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome", J Clin Invest, 116, pp.1784~1792 (2006)
- Wedemeyer I, "Adiponectin inhibits steatotic CD95", Fas up-regulation by hepatocytes: therapeutic implications for hepatitis C, 2009, pp.50, 140~149
- Xu A, "The fat-derived horhorhoadiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice", J Clin Invest, 112, pp.91~100 (2003)
- Hui JM, "Beyond insulin resistance in NASH: TNF-alpha or adiponectin?", Hepatology, 40, pp.46~54 (2004)
- Bugianesi E, "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, pp.3498~3504 (2005)
- Baranova A, "Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance", Obes Surg, 16, pp.1118~1125 (2006)
- Kaser S, "Adiponectin and its receptors in non-alcoholic steatohepatitis", Gut, 54, pp.117~121 (2005)
- Javor ED, "Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy", Hepatology, 41, pp.753~760 (2005)
- Park JH, "Insulin resistance in non-alcoholic fatty liver disease", Korean J Hepatol, 12, pp.16~30 (2006)
- Yang SQ, "Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis", Proc Natl Acad Sci USA, 94, pp.2557~2562 (1997)
- Saxena NK, "Concomitant activation of the JAK", STAT, PI3K, Cancer Res, pp.2007, 67[DOI]
- Osei-Hyiaman D, "Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice", J Clin Invest, 118, pp.3160~3169 (2008)
- Uygun A, "Serum leptin levels in patients with nonalcoholic steatohepatitis", Am J Gastroenterol, 95, pp.3584~3589 (2000)
- Chitturi S, "Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?", Hepatology, 36, pp.403~409 (2002)
- Chalasani N, "Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis?", Am J Gastroenterol, 98, pp.2771~2776 (2003)
- Angulo P, "Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease", J Hepatol, 41, pp.943~949 (2004)
- Schenk S, "Insulin sensitivity: modulation by nutrients and inflammation", J Clin Invest, 118, pp.2992~3002 (2008)
- Tafani M, "Cytochrome c-dependent activation of caspase-3 by tumor necrosis factor requires induction of the mitochondrial permeability transition", Am J Pathol, 156, pp.2111~2121 (2000)
- Wieckowska A, "In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease", Hepatology, 44, pp.27~33 (2006)
- Shapiro L, "The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor", Curr Biol, 8, pp.335~338 (1998)
- Kugelmas M, "Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E", Hepatology, 38, pp.413~419 (2003)
- Pagano C, "Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance", J Clin Endocrinol Metab, 91, pp.1081~1086 (2006)
- Rabe K, "Adipokines and insulin resistance", Mol Med, 14, pp.741~751 (2008)
- Revollo JR, "Nampt", PBEF, Cell Metab, pp.2007, 6[DOI]
- Stefan N, "High circulating retinol- binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans", Diabetes Care, 30, pp.1173~1178 (2007)
- Feldstein AE, "Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice", J Hepatol, 39, pp.978~983 (2003)
- Feldstein AE, "Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis", Gastroenterology, 125, pp.437~443 (2003)
- McAvoy NC, "Review: Non-alcoholic fatty liver disease: natural history, pathogenesis and treatment", Br J Diabet Vasc Dis, 6, pp.251~260 (2006)
