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Non-alcoholic Fatty Liver Disease

Book cover Metabolic Syndrome

Abstract

The metabolic syndrome (MetS), also known as syndrome X or insulin resistance syndrome, is defined by the combination of insulin resistance, abdominal fat distribution, high blood pressure, and dyslipidemia. The coexistence of these risk factors leads to an excess cardiovascular disease morbidity. MetS is an emerging public health and clinical challenge worldwide, caused by the hypercaloric diet and sedentary lifestyle of today’s population.

MetS means a proinflammatory or prothrombic condition, comprising, for example, elevated C-reactive protein (CRP) levels, elevated levels of uric acid, and a shift toward small, dense low-density lipoprotein (LDL) cholesterol particles. An association between the occurrence of MetS and the polycystic ovary syndrome, as well as with nonalcoholic steatohepatitis (NASH), has been described.

In this article, we review current data about the MetS and related diseases. We focus especially on the hepatic damage that is caused by MetS, and thus we describe animal models of nonalcoholic fatty liver disease (NAFLD) giving insights into the mechanisms of NAFLD, and we also provide information about the neoplastic final common path, namely, hepatocellular carcinoma (HCC).

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Abbreviations

AACE:

American Association of Clinic Endocrinologists

ALD:

Alcoholic liver disease

ATF6:

Activating transcription factor-6

BMI:

Body mass index

CARDIA:

Coronary Artery Risk Development in Young Adults

CBS:

Cystathionine beta-synthetase

CCC:

Cholangiocellular carcinoma

CEA:

Carcinoembryonic antigen

CRP:

C-reactive protein

CVD:

Cardiovascular disease

DDC:

3,5-diethoxycarbonyl-1,4-dihydrocollidine

EBV:

Epstein-Barr virus

EGIR:

European Group for the Study of Insulin Resistance

ER:

Endoplasmic reticulum

FATP:

Fatty acid transporter protein

FLC:

Fibrolamellar carcinoma

FLS mice:

Fatty liver Shionogi mice

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HDL:

High-density lipoprotein

HepPar1:

Carbamoyl phosphate synthetase-1

HFDs:

High-fat diets

IDF:

International Diabetes Federation

IGF2:

Insulin-like growth factor 2

IR:

Insulin resistance

JNC 7:

Seventh Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure

LDL:

Low-density lipoprotein

LpL:

Lipoprotein lipase

MAT1A:

Methionine adenosyltransferase 1 alpha

MCD:

Methionine- and choline-deficient diet

MCR4:

Melanocortin 4 receptor

MDBs:

Mallory-Denk bodies

MetS:

Metabolic syndrome

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NCEO/ATP:

National Cholesterol Education Program-Adult Treatment Panel

PERK:

PKR-like ER kinase

PTEN:

Phosphatase and tensin homolog

SH-HCC:

Steatohepatitic HCC

SREBP:

Sterol regulatory element-binding protein

T2DM:

Type 2 diabetes mellitus

VLDL:

Very low-density lipoprotein

WHO:

World Health Organization

References

  • Alb JG,Jr, Cortese JD, Phillips SE, Albin RL, Nagy TR, Hamilton BA, et al. Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia. J Biol Chem 2003 Aug 29;278(35):33501–33518.

    Google Scholar 

  • Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998 Jul;15(7):539–553.

    Google Scholar 

  • Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005 Sep 24-30;366(9491):1059–1062.

    Google Scholar 

  • Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009 Oct 20;120(16):1640–1645.

    Google Scholar 

  • Allgaier HP, Deibert P, Olschewski M, Spamer C, Blum U, Gerok W, et al. Survival benefit of patients with inoperable hepatocellular carcinoma treated by a combination of transarterial chemoembolization and percutaneous ethanol injection – a single-center analysis including 132 patients. Int J Cancer 1998 Dec 18;79(6):601–605.

    Google Scholar 

  • Arsov T, Larter CZ, Nolan CJ, Petrovsky N, Goodnow CC, Teoh NC, et al. Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice. Biochem Biophys Res Commun 2006 Apr 21;342(4):1152–1159.

    Google Scholar 

  • Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999 May;16(5):442–443.

    Google Scholar 

  • Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005 Nov 4;123(3):493–505.

    Google Scholar 

  • Bardag-Gorce F, Riley NE, Nan L, Montgomery RO, Li J, French BA, et al. The proteasome inhibitor, PS-341, causes cytokeratin aggresome formation. Exp Mol Pathol 2004 Feb;76(1):9–16.

    Google Scholar 

  • Bell DS. Understanding the role of insulin resistance for the treatment of diabetes and the reduction of cardiovascular risks. Journal of Gender-Specific Medicine 2002;5(suppl):1S–14S.

    Google Scholar 

  • Bjorntorp P. Heart and soul: stress and the metabolic syndrome. Scand Cardiovasc J 2001 Jul;35(3):172–177.

    Google Scholar 

  • Boison D, Scheurer L, Zumsteg V, Rulicke T, Litynski P, Fowler B, et al. Neonatal hepatic steatosis by disruption of the adenosine kinase gene. Proc Natl Acad Sci U S A 2002 May 14;99(10):6985–6990.

    Google Scholar 

  • Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004 Nov;127(5 Suppl 1):S5–S16.

    Google Scholar 

  • Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of digestive system. International Agency for Research on Cancer 2010;4:205–216.

    Google Scholar 

  • Botezelli JD, Mora RF, Dalia RA, Moura LP, Cambri LT, Ghezzi AC, et al. Exercise counteracts fatty liver disease in rats fed on fructose-rich diet. Lipids Health Dis 2010 Oct 14;9:116-511X-9-116.

    Google Scholar 

  • Boucher E, Forner A, Reig M, Bruix J. New drugs for the treatment of hepatocellular carcinoma. Liver Int 2009 Jan;29 Suppl 1:148–158.

    Google Scholar 

  • Brunt EM, Neuschwander-Tetri BA, Oliver D, Wehmeier KR, Bacon BR. Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens. Hum Pathol 2004 Sep;35(9):1070–1082.

    Google Scholar 

  • Buettner R, Scholmerich J, Bollheimer LC. High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity (Silver Spring) 2007 Apr;15(4):798–808.

    Google Scholar 

  • Cano A, Buque X, Martinez-Una M, Aurrekoetxea I, Menor A, Garcia-Rodriguez JL, et al. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology 2011 Dec;54(6):1975–1986.

    Google Scholar 

  • Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003 May 21;289(19):2560–2572.

    Google Scholar 

  • Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003 May 21;289(19):2560–2572.

    Google Scholar 

  • Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T, et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med 2010 Jan 15;48(2):357–371.

    Google Scholar 

  • Chu PG, Ishizawa S, Wu E, Weiss LM. Hepatocyte antigen as a marker of hepatocellular carcinoma: an immunohistochemical comparison to carcinoembryonic antigen, CD10, and alpha-fetoprotein. Am J Surg Pathol 2002 Aug;26(8):978–988.

    Google Scholar 

  • Ciaraldi TP, Abrams L, Nikoulina S, Mudaliar S, Henry RR. Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 1995 Dec;96(6):2820–2827.

    Google Scholar 

  • Coburn CT, Knapp FF,Jr, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 2000 Oct 20;275(42):32523–32529.

    Google Scholar 

  • Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011 Jun 24;332(6037):1519–1523.

    Google Scholar 

  • Cook WS, Jain S, Jia Y, Cao WQ, Yeldandi AV, Reddy JK, et al. Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidase null mice. Exp Cell Res 2001 Aug 1;268(1):70–76.

    Google Scholar 

  • Craig JR, Peters RL, Edmondson HA. Tumours of the liver and intrahepatic bile ducts. Armed Forces Institute of Pathology 1989.

    Google Scholar 

  • Deen D. Metabolic syndrome: time for action. Am Fam Physician 2004 Jun 15;69(12):2875–2882.

    Google Scholar 

  • Doege H, Grimm D, Falcon A, Tsang B, Storm TA, Xu H, et al. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J Biol Chem 2008 Aug 8;283(32):22186–22192.

    Google Scholar 

  • Duncan GE, Perri MG, Theriaque DW, Hutson AD, Eckel RH, Stacpoole PW. Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults. Diabetes Care 2003 Mar;26(3):557–562.

    Google Scholar 

  • Durko L, Malecka-Panas E. Lifestyle Modifications and Colorectal Cancer. Curr Colorectal Cancer Rep 2014;10:45–54.

    Article  PubMed Central  PubMed  Google Scholar 

  • Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005 Apr 16–22;365(9468):1415–1428.

    Google Scholar 

  • Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. AHA Nutrition Committee. Circulation 1998 Jun 2;97(21):2099–2100.

    Google Scholar 

  • El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999 Mar 11;340(10):745–750.

    Google Scholar 

  • Enzan H, Himeno H, Iwamura S, Onishi S, Saibara T, Yamamoto Y, et al. Alpha-smooth muscle actin-positive perisinusoidal stromal cells in human hepatocellular carcinoma. Hepatology 1994 Apr;19(4):895–903.

    Google Scholar 

  • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001 May 16;285(19):2486–2497.

    Google Scholar 

  • Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003 May–Jun;9(3):237–252.

    Google Scholar 

  • Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A 2009 Sep 8;106(36):15430–15435.

    Google Scholar 

  • Falcon A, Doege H, Fluitt A, Tsang B, Watson N, Kay MA, et al. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol Endocrinol Metab 2010 Sep;299(3):E384–93.

    Google Scholar 

  • Fan CY, Pan J, Usuda N, Yeldandi AV, Rao MS, Reddy JK. Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem 1998 Jun 19;273(25):15639–15645.

    Google Scholar 

  • Ford ES, Giles WH. A comparison of the prevalence of the metabolic syndrome using two proposed definitions. Diabetes Care 2003 Mar;26(3):575–581.

    Google Scholar 

  • Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002 Jan 16;287(3):356–359.

    Google Scholar 

  • Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003 May 22;348(21):2082–2090.

    Google Scholar 

  • Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003 Jan 30;348(5):383–393.

    Google Scholar 

  • Ginsberg HN. Treatment for patients with the metabolic syndrome. Am J Cardiol 2003 Apr 3;91(7A):29E–39E.

    Google Scholar 

  • Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 2001 Dec;86(12):5755–5761.

    Google Scholar 

  • Goudriaan JR, Dahlmans VE, Teusink B, Ouwens DM, Febbraio M, Maassen JA, et al. CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice. J Lipid Res 2003 Dec;44(12):2270–2277.

    Google Scholar 

  • Gregg EW, Cauley JA, Stone K, Thompson TJ, Bauer DC, Cummings SR, et al. Relationship of changes in physical activity and mortality among older women. JAMA 2003 May 14;289(18):2379–2386.

    Google Scholar 

  • Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999 Jun;48(6):1270–1274.

    Google Scholar 

  • Grundy SM, Brewer HB,Jr, Cleeman JI, Smith SC,Jr, Lenfant C, American Heart Association, et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004 Jan 27;109(3):433–438.

    Google Scholar 

  • Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 2006 Mar 21;47(6):1093–1100.

    Google Scholar 

  • Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med 2008 Nov;132(11):1761–1766.

    Google Scholar 

  • Hamelet J, Demuth K, Paul JL, Delabar JM, Janel N. Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice. J Hepatol 2007 Jan;46(1):151–159.

    Google Scholar 

  • Harada M, Strnad P, Toivola DM, Omary MB. Autophagy modulates keratin-containing inclusion formation and apoptosis in cell culture in a context-dependent fashion. Exp Cell Res 2008 May 1;314(8):1753–1764.

    Google Scholar 

  • Hark L, Deen D,Jr. Taking a nutrition history: a practical approach for family physicians. Am Fam Physician 1999 Mar 15;59(6):1521–8, 1531-2.

    Google Scholar 

  • Haybaeck J, Stumptner C, Thueringer A, Kolbe T, Magin TM, Hesse M, et al. Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model. Lab Invest 2012 Jun;92(6):857–867.

    Google Scholar 

  • Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature 2002 Nov 21;420(6913):333–336.

    Google Scholar 

  • Hooper L, Bartlett C, Davey SG, Ebrahim S. Advice to reduce dietary salt for prevention of cardiovascular disease. Cochrane Database Syst Rev 2004;(1)(1):CD003656.

    Google Scholar 

  • Hooper L, Summerbell CD, Higgins JP, Thompson RL, Clements G, Capps N, et al. Reduced or modified dietary fat for preventing cardiovascular disease. Cochrane Database Syst Rev 2001;(3)(3):CD002137.

    Google Scholar 

  • Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004 Jun;113(12):1774–1783.

    Google Scholar 

  • International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome . Available at: http://www.idf.org/metabolic-syndrome.

  • Ishak KG, Anthony PP, Sobin LH. Histological typing of tumours of the liver. Springer 1999.

    Google Scholar 

  • Itoh M, Suganami T, Nakagawa N, Tanaka M, Yamamoto Y, Kamei Y, et al. Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am J Pathol 2011 Nov;179(5):2454–2463.

    Google Scholar 

  • Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A 2004 May 11;101(19):7281–7286.

    Google Scholar 

  • Jenkins DJ, Kendall CW, Augustin LS, Vuksan V. High-complex carbohydrate or lente carbohydrate foods? Am J Med 2002 Dec 30;113 Suppl 9B:30S–37S.

    Google Scholar 

  • Jiang L, You J, Yu X, Gonzalez L, Yu Y, Wang Q, et al. Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis. Proc Natl Acad Sci U S A 2008 Nov 25;105(47):18619–18624.

    Google Scholar 

  • Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014;2014:943162.

    PubMed Central  PubMed  Google Scholar 

  • Kava R, Greenwood MRC, Johnson PR. Zucker (fa/fa) Rat. ILAR Journal 1990;32:4–8.

    Article  Google Scholar 

  • Kawasaki T, Igarashi K, Koeda T, Sugimoto K, Nakagawa K, Hayashi S, et al. Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. J Nutr 2009 Nov;139(11):2067–2071.

    Google Scholar 

  • Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992 Nov;41(11):1422–1428.

    Google Scholar 

  • Keller C, Trevino RP. Effects of two frequencies of walking on cardiovascular risk factor reduction in Mexican American women. Res Nurs Health 2001 Oct;24(5):390–401.

    Google Scholar 

  • Kessler SM, Simon Y, Gemperlein K, Gianmoena K, Cadenas C, Zimmer V, et al. Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma. Int J Mol Sci 2014 Apr 4;15(4):5762–5773.

    Google Scholar 

  • Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001 Jun 19;98(13):7522–7527.

    Google Scholar 

  • Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000 Mar 24;275(12):8456–8460.

    Google Scholar 

  • Kimura Y, Hyogo H, Ishitobi T, Nabeshima Y, Arihiro K, Chayama K. Postprandial insulin secretion pattern is associated with histological severity in non-alcoholic fatty liver disease patients without prior known diabetes mellitus. J Gastroenterol Hepatol 2011 Mar;26(3):517–522.

    Google Scholar 

  • Kimura H, Nakajima T, Kagawa K, Deguchi T, Kakusui M, Katagishi T, et al. Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry. Liver 1998 Feb;18(1):14–19.

    Google Scholar 

  • Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002 Feb 7;346(6):393–403.

    Google Scholar 

  • Koh HJ, Lee SM, Son BG, Lee SH, Ryoo ZY, Chang KT, et al. Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J Biol Chem 2004 Sep 17;279(38):39968–39974.

    Google Scholar 

  • Kohli R, Kirby M, Xanthakos SA, Softic S, Feldstein AE, Saxena V, et al. High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis. Hepatology 2010 Sep;52(3):934–944.

    Google Scholar 

  • Kojiro M, Sugihara S, Kakizoe S, Nakashima O, Kiyomatsu K. Hepatocellular carcinoma with sarcomatous change: a special reference to the relationship with anticancer therapy. Cancer Chemother Pharmacol 1989;23 Suppl:S4–8.

    Article  PubMed  Google Scholar 

  • Koutnikova H, Cock TA, Watanabe M, Houten SM, Champy MF, Dierich A, et al. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice. Proc Natl Acad Sci U S A 2003 Nov 25;100(24):14457–14462.

    Google Scholar 

  • Kraegen EW, Clark PW, Jenkins AB, Daley EA, Chisholm DJ, Storlien LH. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 1991 Nov;40(11):1397–1403.

    Google Scholar 

  • Kurogi M, Nakashima O, Miyaaki H, Fujimoto M, Kojiro M. Clinicopathological study of scirrhous hepatocellular carcinoma. J Gastroenterol Hepatol 2006 Sep;21(9):1470–1477.

    Google Scholar 

  • Kuwajima M, Kono N, Horiuchi M, Imamura Y, Ono A, Inui Y, et al. Animal model of systemic carnitine deficiency: analysis in C3H-H-2 degrees strain of mouse associated with juvenile visceral steatosis. Biochem Biophys Res Commun 1991 Feb 14;174(3):1090–1094.

    Google Scholar 

  • Laggai S, Kessler SM, Boettcher S, Lebrun V, Gemperlein K, Lederer E, et al. The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis. J Lipid Res 2014 Apr 22;55(6):1087–1097.

    Google Scholar 

  • Laurent V, Kimble A, Peng B, Zhu P, Pintar JE, Steiner DF, et al. Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion. Proc Natl Acad Sci U S A 2002 Mar 5;99(5):3087–3092.

    Google Scholar 

  • Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 2003 Jan 31;278(5):2896–2902.

    Google Scholar 

  • Liu S, Manson JE. Dietary carbohydrates, physical inactivity, obesity, and the ‘metabolic syndrome’ as predictors of coronary heart disease. Curr Opin Lipidol 2001 Aug;12(4):395–404.

    Google Scholar 

  • Lopez-Candales A. Metabolic syndrome X: a comprehensive review of the pathophysiology and recommended therapy. J Med 2001;32(5-6):283–300.

    CAS  PubMed  Google Scholar 

  • Lu SC, Alvarez L, Huang ZZ, Chen L, An W, Corrales FJ, et al. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci U S A 2001 May 8;98(10):5560–5565.

    Google Scholar 

  • Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 2007 Feb;11(2):119–132.

    Google Scholar 

  • Ma KL, Ruan XZ, Powis SH, Chen Y, Moorhead JF, Varghese Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 2008 Sep;48(3):770–781.

    Google Scholar 

  • Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR, Berry DP. Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer 2007 Apr;43(6):979–992.

    Google Scholar 

  • Manchanayake J, Chitturi S, Nolan C, Farrell GC. Postprandial hyperinsulinemia is universal in non-diabetic patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2011 Mar;26(3):510–516.

    Google Scholar 

  • Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 2007 Nov;46(5):1392–1403.

    Google Scholar 

  • McInnis KJ, Franklin BA, Rippe JM. Counseling for physical activity in overweight and obese patients. Am Fam Physician 2003 Mar 15;67(6):1249–1256.

    Google Scholar 

  • Merriman RB, Aouizerat BE, Bass NM. Genetic influences in nonalcoholic fatty liver disease. J Clin Gastroenterol 2006 Mar;40 Suppl 1:S30–3.

    Google Scholar 

  • Merkel M, Weinstock PH, Chajek-Shaul T, Radner H, Yin B, Breslow JL, et al. Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia. J Clin Invest 1998 Sep 1;102(5):893–901.

    Google Scholar 

  • Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, et al. Life without white fat: a transgenic mouse. Genes Dev 1998 Oct 15;12(20):3168–3181.

    Google Scholar 

  • Morton NM, Seckl JR. 11beta-Hydroxysteroid Dehydrogenase Type 1 and Obesity. Front Horm Res 2008;36:146–164.

    Article  CAS  PubMed  Google Scholar 

  • National Institutes of Health, Bethesda, MD. Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive Summary. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. Accessed March 18, 2004.

  • Nemoto Y, Toda K, Ono M, Fujikawa-Adachi K, Saibara T, Onishi S, et al. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest 2000 Jun;105(12):1819–1825.

    Google Scholar 

  • Nemolato S, Fanni D, Naccarato AG, Ravarino A, Bevilacqua G, Faa G. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature. World J Gastroenterol 2008 Aug 7;14(29):4694–4696.

    Google Scholar 

  • Okumura K, Ikejima K, Kon K, Abe W, Yamashina S, Enomoto N, et al. Exacerbation of dietary steatohepatitis and fibrosis in obese, diabetic KK-A(y) mice. Hepatol Res 2006 Nov;36(3):217–228.

    Google Scholar 

  • Olijhoek JK, van der Graaf Y, Banga JD, Algra A, Rabelink TJ, Visseren FL, et al. The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J 2004 Feb;25(4):342–348.

    Google Scholar 

  • Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004 Oct 15;306(5695):457–461.

    Google Scholar 

  • Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO,3rd, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003 Jan 28;107(3):499–511.

    Google Scholar 

  • Pereira MA, Jacobs DR,Jr, Van Horn L, Slattery ML, Kartashov AI, Ludwig DS. Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA Study. JAMA 2002 Apr 24;287(16):2081–2089.

    Google Scholar 

  • Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004 Feb 12;350(7):664–671.

    Google Scholar 

  • Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002 May;109(10):1345–1350.

    Google Scholar 

  • Petrella RJ, Wight D. An office-based instrument for exercise counseling and prescription in primary care. The Step Test Exercise Prescription (STEP). Arch Fam Med 2000 Apr;9(4):339–344.

    Google Scholar 

  • Piper ML, Unger EK, Myers MG,Jr, Xu AW. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol Endocrinol 2008 Mar;22(3):751–759.

    Google Scholar 

  • Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008 Mar;118(3):829–838.

    Google Scholar 

  • Pouliot MC, Despres JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, et al. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol 1994 Mar 1;73(7):460–468.

    Google Scholar 

  • Raabe M, Veniant MM, Sullivan MA, Zlot CH, Bjorkegren J, Nielsen LB, et al. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J Clin Invest 1999 May;103(9):1287–1298.

    Google Scholar 

  • Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J, Green RM. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 2008 May;49(5):1068–1076.

    Google Scholar 

  • Ross SR, Graves RA, Spiegelman BM. Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity. Genes Dev 1993 Jul;7(7B):1318–1324.

    Google Scholar 

  • Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med 2000 Jul 18;133(2):92–103.

    Google Scholar 

  • Rossetti L, Barzilai N, Chen W, Harris T, Yang D, Rogler CE. Hepatic overexpression of insulin-like growth factor-II in adulthood increases basal and insulin-stimulated glucose disposal in conscious mice. J Biol Chem 1996 Jan 5;271(1):203–208.

    Google Scholar 

  • Salomao M, Remotti H, Vaughan R, Siegel AB, Lefkowitch JH, Moreira RK. The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis. Hum Pathol 2012 May;43(5):737–746.

    Google Scholar 

  • Salomao M, Yu WM, Brown RS,Jr, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am J Surg Pathol 2010 Nov;34(11):1630–1636.

    Google Scholar 

  • Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004 Jul 30;279(31):32345–32353.

    Google Scholar 

  • Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 2007 Apr;87(2):507–520.

    Google Scholar 

  • Schattenberg JM, Galle PR. Animal models of non-alcoholic steatohepatitis: of mice and man. Dig Dis 2010;28(1):247–254.

    Article  CAS  PubMed  Google Scholar 

  • Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 2006 Jan;43(1):163–172.

    Google Scholar 

  • Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998 Oct 15;12(20):3182–3194.

    Google Scholar 

  • Simon Y, Kessler SM, Bohle RM, Haybaeck J, Kiemer AK. The insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IGF2BP2-2 as a promoter of NAFLD and HCC? Gut 2014 May;63(5):861–863.

    Google Scholar 

  • Slentz CA, Duscha BD, Johnson JL, Ketchum K, Aiken LB, Samsa GP, et al. Effects of the amount of exercise on body weight, body composition, and measures of central obesity: STRRIDE – a randomized controlled study. Arch Intern Med 2004 Jan 12;164(1):31–39.

    Google Scholar 

  • Soga M, Hashimoto S, Kishimoto Y, Hirasawa T, Makino S, Inagaki S. Insulin resistance, steatohepatitis, and hepatocellular carcinoma in a new congenic strain of Fatty Liver Shionogi (FLS) mice with the Lep(ob) gene. Exp Anim 2010;59(4):407–419.

    Article  CAS  PubMed  Google Scholar 

  • Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected. Proc Natl Acad Sci U S A 2004 Feb 17;101(7):2082–2087.

    Google Scholar 

  • Sugo H, Takamori S, Kojima K, Beppu T, Futagawa S. The significance of p53 mutations as an indicator of the biological behavior of recurrent hepatocellular carcinomas. Surg Today 1999;29(9):849–855.

    Article  CAS  PubMed  Google Scholar 

  • Szapary PO, Hark LA, Burke FM. The metabolic syndrome: a new focus for lifestyle modification. Patient Care 2002;36:75–88.

    Google Scholar 

  • Takahashi A, Shimano H, Nakagawa Y, Yamamoto T, Motomura K, Matsuzaka T, et al. Transgenic mice overexpressing SREBP-1a under the control of the PEPCK promoter exhibit insulin resistance, but not diabetes. Biochim Biophys Acta 2005 Jun 10;1740(3):427–433.

    Google Scholar 

  • Takamatsu S, Noguchi N, Kudoh A, Nakamura N, Kawamura T, Teramoto K, et al. Influence of risk factors for metabolic syndrome and non-alcoholic fatty liver disease on the progression and prognosis of hepatocellular carcinoma. Hepatogastroenterology 2008 Mar–Apr;55(82–83):609–614.

    Google Scholar 

  • 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 2008 Nov;295(5):G987–95.

    Google Scholar 

  • Torbenson M. Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol 2007 May;14(3):217–223.

    Google Scholar 

  • Trak-Smayra V, Paradis V, Massart J, Nasser S, Jebara V, Fromenty B. Pathology of the liver in obese and diabetic ob/ob and db/db mice fed a standard or high-calorie diet. Int J Exp Pathol 2011 Dec;92(6):413–421.

    Google Scholar 

  • Trichopoulou A, Costacou T, Bamia C, Trichopoulos D, deKoning L, Anand SS. Adherence to a Mediterranean diet and survival in a Greek population. Vascular Medicine 2004;9(2):145–146.

    Article  Google Scholar 

  • Trichopoulou A, Costacou T, Bamia C, Trichopoulos D, deKoning L, Anand SS. Adherence to a Mediterranean diet and survival in a Greek population. New England Journal of Medicine 2003;348:2599–2608.

    Article  PubMed  Google Scholar 

  • Tybl E, Shi FD, Kessler SM, Tierling S, Walter J, Bohle RM, et al. Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype. J Hepatol 2011 May;54(5):994–1001.

    Google Scholar 

  • U.S. Preventive Services Task Force. Behavioral counseling in primary care to promote a healthy diet: recommendations and rationale. Am J Prev Med 2003 Jan;24(1):93–100.

    Google Scholar 

  • U.S. Preventive Services Task Force. Behavioral counseling in primary care to promote physical activity: recommendation and rationale. Ann Intern Med 2002 Aug 6;137(3):205–207.

    Google Scholar 

  • Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 2003 Oct;94(10):851–857.

    Google Scholar 

  • Uka K, Aikata H, Takaki S, Shirakawa H, Jeong SC, Yamashina K, et al. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 2007 Jan 21;13(3):414–420.

    Google Scholar 

  • Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000 Jul;106(2):253–262.

    Google Scholar 

  • Varela-Rey M, Embade N, Ariz U, Lu SC, Mato JM, Martinez-Chantar ML. Non-alcoholic steatohepatitis and animal models: understanding the human disease. Int J Biochem Cell Biol 2009 May;41(5):969–976.

    Google Scholar 

  • Vega GL. Results of Expert Meetings: Obesity and Cardiovascular Disease. Obesity, the metabolic syndrome, and cardiovascular disease. Am Heart J 2001 Dec;142(6):1108–1116.

    Google Scholar 

  • Vollmer WM, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, et al. Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial. Ann Intern Med 2001 Dec 18;135(12):1019–1028.

    Google Scholar 

  • Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 1996 Dec;111(6):1645–1653.

    Google Scholar 

  • Yamamoto K, Takahara K, Oyadomari S, Okada T, Sato T, Harada A, et al. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell 2010 Sep 1;21(17):2975–2986.

    Google Scholar 

  • Yanagitani A, Yamada S, Yasui S, Shimomura T, Murai R, Murawaki Y, et al. Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice. Hepatology 2004 Aug;40(2):366–375.

    Google Scholar 

  • Zatloukal B, Kufferath I, Thueringer A, Landegren U, Zatloukal K, Haybaeck J. Sensitivity and specificity of in situ proximity ligation for protein interaction analysis in a model of steatohepatitis with Mallory-Denk bodies. PLoS One 2014 May 5;9(5):e96690.

    Google Scholar 

  • Zhou Q, Ji X, Chen L, Greenberg HB, Lu SC, Omary MB. Keratin mutation primes mouse liver to oxidative injury. Hepatology 2005 Mar;41(3):517–525.

    Google Scholar 

  • Zhou YC, Davey HW, McLachlan MJ, Xie T, Waxman DJ. Elevated basal expression of liver peroxisomal beta-oxidation enzymes and CYP4A microsomal fatty acid omega-hydroxylase in STAT5b(-/-) mice: cross-talk in vivo between peroxisome proliferator-activated receptor and signal transducer and activator of transcription signaling pathways. Toxicol Appl Pharmacol 2002 Jul 1;182(1):1–10.

    Google Scholar 

  • Zhu X, Song J, Mar MH, Edwards LJ, Zeisel SH. Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline. Biochem J 2003 Mar 15;370(Pt 3):987–993.

    Google Scholar 

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Smolle, E., Kessler, S.M., Golob, N., Haybaeck, J. (2015). Non-alcoholic Fatty Liver Disease. In: Ahima, R. (eds) Metabolic Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-319-12125-3_36-1

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  1. Latest

    Non-alcoholic Fatty Liver Disease
    Published:
    19 September 2023

    DOI: https://doi.org/10.1007/978-3-319-12125-3_36-2

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    Non-alcoholic Fatty Liver Disease
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    15 July 2015

    DOI: https://doi.org/10.1007/978-3-319-12125-3_36-1