Abnormalities of Lipid Metabolism in Nonalcoholic Fatty Liver Disease

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common liver abnormality in the United States and is strongly associated with the metabolic syndrome. Although many of the risk factors are well defined, the pathogenesis of NAFLD remains poorly understood. Recent studies have implicated several important cellular processes and signaling pathways that are affected by abnormal lipid metabolism, resulting in specific biochemical, histological, and clinical changes associated with NAFLD. Pharmacotherapy for NAFLD is limited and treatments are mainly to minimize risk factors. Understanding the disease pathogenesis is therefore important in identifying individuals with increased susceptibility for disease progression so lifestyle and risk modifications can be initiated early on. In this review, recent advances in the study of abnormal lipid metabolism and its impacts on histology and dysregulation of various cellular processes implicated in the genesis of NAFLD will be discussed.

KEYWORDS

Nonalcoholic steatohepatitis - metabolic syndrome - insulin resistance - de novo lipogenesis - hepatic steatosis

REFERENCES

• 1 Brunt E M. Nonalcoholic steatohepatitis: definition and pathology.  Semin Liver Dis. 2001;  21(1) 3-16
• 2 Browning J D, Szczepaniak L S, Dobbins R et al.. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.  Hepatology. 2004;  40(6) 1387-1395
• 3 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;  285(19) 2486-2497
• 4 Hsiao P J, Kuo K K, Shin S J et al.. Significant correlations between severe fatty liver and risk factors for metabolic syndrome.  J Gastroenterol Hepatol. 2007;  22(12) 2118-2123
• 5 Puri P, Baillie R A, Wiest M M et al.. A lipidomic analysis of nonalcoholic fatty liver disease.  Hepatology. 2007;  46(4) 1081-1090
• 6 Wang D, Wei Y, Pagliassotti M J. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis.  Endocrinology. 2006;  147(2) 943-951
• 7 Wei Y, Wang D, Topczewski F, Pagliassotti M J. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.  Am J Physiol Endocrinol Metab. 2006;  291(2) E275-E281
• 8 Sanyal A J, Campbell-Sargent C, Mirshahi F et al.. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.  Gastroenterology. 2001;  120(5) 1183-1192
• 9 Adams L A, Sanderson S, Lindor K D, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.  J Hepatol. 2005;  42(1) 132-138
• 10 Evans R M, Barish G D, Wang Y X. PPARs and the complex journey to obesity.  Nat Med. 2004;  10(4) 355-361
• 11 Donnelly K L, Smith C I, Schwarzenberg S J, Jessurun J, Boldt M D, Parks E J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.  J Clin Invest. 2005;  115(5) 1343-1351
• 12 Bugianesi E, Leone N, Vanni E et al.. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.  Gastroenterology. 2002;  123(1) 134-140
• 13 Matsusue K, Haluzik M, Lambert G et al.. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.  J Clin Invest. 2003;  111(5) 737-747
• 14 Browning J D, Horton J D. Molecular mediators of hepatic steatosis and liver injury.  J Clin Invest. 2004;  114(2) 147-152
• 15 Sekiya M, Yahagi N, Matsuzaka T et al.. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.  Hepatology. 2003;  38(6) 1529-1539
• 16 Magana M M, Lin S S, Dooley K A, Osborne T F. Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins.  J Lipid Res. 1997;  38(8) 1630-1638
• 17 Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes.  Biochem J. 2000;  350(Pt 2) 389-393
• 18 Fleischmann M, Iynedjian P B. Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt.  Biochem J. 2000;  349(Pt 1) 13-17
• 19 Ribot J, Rantala M, Kesaniemi Y A, Palou A, Savolainen M J. Weight loss reduces expression of SREBP1c/ADD1 and PPARgamma2 in adipose tissue of obese women.  Pflugers Arch. 2001;  441(4) 498-505
• 20 Mater M K, Thelen A P, Pan D A, Jump D B. Sterol response element-binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty acid suppression of hepatic S14 gene transcription.  J Biol Chem. 1999;  274(46) 32725-32732
• 21 Hashimoto T, Cook W S, Qi C, Yeldandi A V, Reddy J K, Rao M S. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.  J Biol Chem. 2000;  275(37) 28918-28928
• 22 Iizuka K, Bruick R K, Liang G, Horton J D, Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.  Proc Natl Acad Sci U S A. 2004;  101(19) 7281-7286
• 23 Yamashita H, Takenoshita M, Sakurai M et al.. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver.  Proc Natl Acad Sci U S A. 2001;  98(16) 9116-9121
• 24 Ishii S, Iizuka K, Miller B C, Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription.  Proc Natl Acad Sci U S A. 2004;  101(44) 15597-15602
• 25 Dentin R, Benhamed F, Hainault I et al.. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.  Diabetes. 2006;  55(8) 2159-2170
• 26 Cha J Y, Repa J J. The liver X receptor (LXR) and hepatic lipogenesis: the carbohydrate-response element-binding protein is a target gene of LXR.  J Biol Chem. 2007;  282(1) 743-751
• 27 Mitro N, Mak P A, Vargas L et al.. The nuclear receptor LXR is a glucose sensor.  Nature. 2007;  445(7124) 219-223
• 28 Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-Puig A J, Flier J S. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma): differential activity of PPARgamma1 and -2 isoforms and influence of insulin.  J Biol Chem. 1997;  272(32) 20230-20235
• 29 Zhang Y L, Hernandez-Ono A, Siri P et al.. Aberrant hepatic expression of PPARgamma2 stimulates hepatic lipogenesis in a mouse model of obesity, insulin resistance, dyslipidemia, and hepatic steatosis.  J Biol Chem. 2006;  281(49) 37603-37615
• 30 Ren D, Collingwood T N, Rebar E J, Wolffe A P, Camp H S. PPAR gamma knockdown by engineered transcription factors: exogenous PPAR gamma 2 but not PPAR gamma 1 reactivates adipogenesis.  Genes Dev. 2002;  16 27-32
• 31 Vidal-Puig A J, Considine R V, Jimenez-Linan M et al.. Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids.  J Clin Invest. 1997;  99(10) 2416-2422
• 32 Yu S, Matsusue K, Kashireddy P et al.. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression.  J Biol Chem. 2003;  278(1) 498-505
• 33 James W P. Overweight and obesity. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL WHO Comparative Quantification of Health Risks. Vol. 1. Geneva; World Health Organization 2003
• 34 Prunet-Marcassus B, Cousin B, Caton D, Andre M, Penicaud L, Casteilla L. From heterogeneity to plasticity in adipose tissues: site-specific differences.  Exp Cell Res. 2006;  312(6) 727-736
• 35 Curat C A, Wegner V, Sengenes C et al.. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin.  Diabetologia. 2006;  49(4) 744-747
• 36 Rae C, Robertson S A, Taylor J M, Graham A. Resistin induces lipolysis and re-esterification of triacylglycerol stores, and increases cholesteryl ester deposition, in human macrophages.  FEBS Lett. 2007;  581(25) 4877-4883
• 37 Gu N, Guo X R, Ni Y H, Liu F, Fei L, Chen R H. Overexpression of resistin affect 3T3–L1 adipocyte lipid metabolism.  Zhonghua Yi Xue Yi Chuan Xue Za Zhi.. 2007;  24(3) 251-255
• 38 Ort T, Arjona A A, MacDougall J R et al.. Recombinant human FIZZ3/resistin stimulates lipolysis in cultured human adipocytes, mouse adipose explants, and normal mice.  Endocrinology. 2005;  146(5) 2200-2209
• 39 Li J, Yu X, Pan W, Unger R H. Gene expression profile of rat adipose tissue at the onset of high-fat-diet obesity.  Am J Physiol Endocrinol Metab. 2002;  282(6) E1334-E1341
• 40 Rao M S, Reddy J K. PPARalpha in the pathogenesis of fatty liver disease.  Hepatology. 2004;  40(4) 783-786
• 41 Reddy J K, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system.  Annu Rev Nutr. 2001;  21 193-230
• 42 Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.  Mitochondrion. 2006;  6(1) 1-28
• 43 Solis Herruzo J A, Garcia Ruiz I, Perez Carreras M, Munoz Yague M T. Non-alcoholic fatty liver disease: from insulin resistance to mitochondrial dysfunction.  Rev Esp Enferm Dig. 2006;  98(11) 844-874
• 44 Nakamuta M, Kohjima M, Morizono S et al.. Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.  Int J Mol Med. 2005;  16(4) 631-635
• 45 Asayama K, Sandhir R, Sheikh F G, Hayashibe H, Nakane T, Singh I. Increased peroxisomal fatty acid beta-oxidation and enhanced expression of peroxisome proliferator-activated receptor-alpha in diabetic rat liver.  Mol Cell Biochem. 1999;  194(1–2) 227-234
• 46 Kohjima M, Enjoji M, Higuchi N et al.. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.  Int J Mol Med. 2007;  20(3) 351-358
• 47 Petrosillo G, Portincasa P, Grattagliano I et al.. Mitochondrial dysfunction in rat with nonalcoholic fatty liver involvement of complex I, reactive oxygen species and cardiolipin.  Biochim Biophys Acta. 2007;  1767(10) 1260-1267
• 48 Paradies G, Petrosillo G, Pistolese M, Ruggiero F M. Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage.  Gene. 2002;  286(1) 135-141
• 49 Pessayre D, Mansouri A, Fromenty B. Nonalcoholic steatosis and steatohepatitis: V. Mitochondrial dysfunction in steatohepatitis.  Am J Physiol Gastrointest Liver Physiol. 2002;  282(2) G193-G199
• 50 Hensley K, Kotake Y, Sang H et al.. Dietary choline restriction causes complex I dysfunction and increased H(2)O(2) generation in liver mitochondria.  Carcinogenesis. 2000;  21(5) 983-989
• 51 Yang Z, Lantz P E, Ibdah J A. Post-mortem analysis for two prevalent beta-oxidation mutations in sudden infant death.  Pediatr Int. 2007;  49(6) 883-887
• 52 Savage D B, Choi C S, Samuel V T et al.. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.  J Clin Invest. 2006;  116(3) 817-824
• 53 Fan C Y, Pan J, Usuda N, Yeldandi A V, Rao M S, Reddy J K. 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;  273(25) 15639-15645
• 54 Ip E, Farrell G C, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.  Hepatology. 2003;  38(1) 123-132
• 55 Kashireddy P V, Rao M S. Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis.  Hepatol Res. 2004;  30(2) 104-110
• 56 Seo Y S, Kim J H, Jo N Y et al.. PPAR agonists treatment is effective in a nonalcoholic fatty liver disease animal model by modulating fatty-acid metabolic enzymes.  J Gastroenterol Hepatol. 2008;  23(1) 102-109
• 57 Harano Y, Yasui K, Toyama T et al.. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver.  Liver Int. 2006;  26(5) 613-620
• 58 Unger R H. Lipotoxic diseases.  Annu Rev Med. 2002;  53 319-336
• 59 Listenberger L L, Han X, Lewis S E et al.. Triglyceride accumulation protects against fatty acid-induced lipotoxicity.  Proc Natl Acad Sci U S A. 2003;  100(6) 3077-3082
• 60 Sanyal A J. AGA technical review on nonalcoholic fatty liver disease.  Gastroenterology. 2002;  123(5) 1705-1725
• 61 Weltman M D, Farrell G C, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation.  Gastroenterology. 1996;  111(6) 1645-1653
• 62 Chalasani N, Gorski J C, Asghar M S et al.. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis.  Hepatology. 2003;  37(3) 544-550
• 63 Ekstrom G, Ingelman-Sundberg M. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1).  Biochem Pharmacol. 1989;  38(8) 1313-1319
• 64 Schattenberg J M, Wang Y, Singh R, Rigoli R M, Czaja M J. Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling.  J Biol Chem. 2005;  280(11) 9887-9894
• 65 Diehl A M, Li Z P, Lin H Z, Yang S Q. Cytokines and the pathogenesis of non-alcoholic steatohepatitis.  Gut. 2005;  54(2) 303-306
• 66 Feldstein A E, Werneburg N W, Canbay A et al.. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.  Hepatology. 2004;  40(1) 185-194
• 67 Furukawa S, Fujita T, Shimabukuro M et al.. Increased oxidative stress in obesity and its impact on metabolic syndrome.  J Clin Invest. 2004;  114(12) 1752-1761
• 68 de Pablo M A, Alvarez de Cienfuegos G. Modulatory effects of dietary lipids on immune system functions.  Immunol Cell Biol. 2000;  78(1) 31-39
• 69 Yin H, Porter N A. New insights regarding the autoxidation of polyunsaturated fatty acids.  Antioxid Redox Signal. 2005;  7(1–2) 170-184
• 70 Kukoba T V, Shysh A M, Moibenko O O, Kotsiuruba A V, Kharchenko O V. The effects of omega-3 polyunsaturated fatty acids on lipid peroxidation.  Fiziol Zh. 2005;  51(1) 26-32
• 71 Sweeney B, Puri P, Reen D J. Modulation of immune cell function by polyunsaturated fatty acids.  Pediatr Surg Int. 2005;  21(5) 335-340
• 72 Puri P, Natarajan R, Maher J W, Kellum J M, Sanyal A J. Differential activation and dysregulation of unfolded protein response (UPR) in nonalcoholic fatty liver disease (NAFLD).  Hepatology. 2006;  44(suppl 1) 213A
• 73 Malhi H, Bronk S F, Werneburg N W, Gores G J. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.  J Biol Chem. 2006;  281(17) 12093-12101
• 74 Osei-Hyiaman D, DePetrillo M, Pacher P et al.. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity.  J Clin Invest. 2005;  115(5) 1298-1305
• 75 Siegmund S V, Uchinami H, Osawa Y, Brenner D A, Schwabe R F. Anandamide induces necrosis in primary hepatic stellate cells.  Hepatology. 2005;  41(5) 1085-1095
• 76 Esau C, Davis S, Murray S F et al.. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.  Cell Metab. 2006;  3(2) 87-98
• 77 Esau C, Kang X, Peralta E et al.. MicroRNA-143 regulates adipocyte differentiation.  J Biol Chem. 2004;  279(50) 52361-52365
• 78 Poy M N, Eliasson L, Krutzfeldt J et al.. A pancreatic islet-specific microRNA regulates insulin secretion.  Nature. 2004;  432(7014) 226-230
• 79 Ambros V. The functions of animal microRNAs.  Nature. 2004;  431(7006) 350-355
• 80 Nilsen T W. Mechanisms of microRNA-mediated gene regulation in animal cells.  Trends Genet. 2007;  23(5) 243-249
• 81 Alvarez-Garcia I, Miska E A. MicroRNA functions in animal development and human disease.  Development. 2005;  132(21) 4653-4662
• 82 Thompson B J, Cohen S M. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila.  Cell. 2006;  126(4) 767-774
• 83 Jopling C L, Norman K L, Sarnow P. Positive and negative modulation of viral and cellular mRNAs by liver-specific microRNA miR-122.  Cold Spring Harb Symp Quant Biol. 2006;  71 369-376
• 84 Krutzfeldt J, Rajewsky N, Braich R et al.. Silencing of microRNAs in vivo with “antagomirs”.  Nature. 2005;  438(7068) 685-689
• 85 Younossi Z M, Gorreta F, Ong J P et al.. Hepatic gene expression in patients with obesity-related non-alcoholic steatohepatitis.  Liver Int. 2005;  25(4) 760-771
• 86 Sreekumar R, Rosado B, Rasmussen D, Charlton M. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis.  Hepatology. 2003;  38(1) 244-251
• 87 Bernard S, Touzet S, Personne I et al.. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes.  Diabetologia. 2000;  43(8) 995-999
• 88 Namikawa C, Shu-Ping Z, Vyselaar J R et al.. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis.  J Hepatol. 2004;  40(5) 781-786
• 89 Gambino R, Cassader M, Pagano G, Durazzo M, Musso G. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH?.  Hepatology. 2007;  45(5) 1097-1107
• 90 Yu X X, Murray S F, Pandey S K et al.. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice.  Hepatology. 2005;  42(2) 362-371
• 91 Araya J, Rodrigo R, Videla L A et al.. Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease.  Clin Sci (Lond). 2004;  106(6) 635-643
• 92 Kaye S A, Folsom A R, Sprafka J M, Prineas R J, Wallace R B. Increased incidence of diabetes mellitus in relation to abdominal adiposity in older women.  J Clin Epidemiol. 1991;  44(3) 329-334
• 93 Golay A, Chen N, Chen Y D, Hollenbeck C, Reaven G M. Effect of central obesity on regulation of carbohydrate metabolism in obese patients with varying degrees of glucose tolerance.  J Clin Endocrinol Metab. 1990;  71(5) 1299-1304
• 94 Despres J P. Abdominal obesity as important component of insulin-resistance syndrome.  Nutrition. 1993;  9(5) 452-459
• 95 Cheung O, Kapoor A, Puri P et al.. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome.  Hepatology. 2007;  46(4) 1091-100