J Korean Diabetes.  2014 Jun;15(2):65-70. 10.4093/jkd.2014.15.2.65.

Definition, Pathogenesis, and Natural Progress of Non-alcoholic Fatty Liver Disease

• Jeon JH
• Park KG

• KMID: 2173896
• DOI: http://doi.org/10.4093/jkd.2014.15.2.65

Abstract

Non-alcoholic fatty liver disease (NAFLD) is emerging as a world-wide health problem and is currently recognized as a hepatic manifestation of metabolic syndrome. It is an umbrella term to describe a wide range of diseases from simple steatosis to non-alcoholic hepatosteatosis (NASH) and NSAH-related liver cirrhosis. NAFLD is mainly associated with insulin resistance which allows increased free fatty acid (FFA) flux to the liver by increasing lipolysis from adipose tissue, triggering macrophage/immune activation, decreasing skeletal muscle glucose uptake, and increasing de novo lipogenesis. Increased FFA pool in the liver, in turn, increases lipotoxic intermediates, such as ceramides, diacylglycerols, and lysophosphatidylcholines, which are responsible for mitochondrial dysfunction and endoplasmic reticulum stress, resulting in inflammation of the liver. When inflammation is severe enough to affect stellate cells, hepatic fibrosis can be induced.

Keyword

Free fatty acid; Insulin resistance; Non-alcoholic fatty liver disease; Obesity

MeSH Terms

Adipose Tissue
Ceramides
Diglycerides
Endoplasmic Reticulum Stress
Fatty Liver*
Fibrosis
Glucose
Hepatic Stellate Cells
Inflammation
Insulin Resistance
Lipogenesis
Lipolysis
Liver
Liver Cirrhosis
Lysophosphatidylcholines
Muscle, Skeletal
Obesity
Ceramides
Diglycerides
Glucose
Lysophosphatidylcholines

Reference

References

1. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011; 332:1519–23.

2. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. The diagnosis and management of nonalcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012; 107:811–26.

3. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005; 288:E462–8.

4. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis. 2009; 13:511–31.

5. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010; 51:1820–32.

6. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005; 129:113–21.

7. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006; 44:865–73.

8. Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, Younossi ZM. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009; 7:234–8.

9. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010; 59:1410–5.

10. Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014; 59:713–23.

11. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009; 48:1–26.

12. Menezes AL, Pereira MP, Buzelle SL, Dos Santos MP, de França SA, Baviera AM, Andrade CM, Garófalo MA, Kettelhut Ido C, Chaves VE, Kawashita NH. A low-protein, high-carbohydrate diet increases de novo fatty acid synthesis from glycerol and glycerokinase content in the liver of growing rats. Nutr Res. 2013; 33:494–502.

13. Laplante M, Sabatini DM. mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci U S A. 2010; 107:3281–2.

14. Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010; 12(Suppl 2):83–92.

15. Foufelle F, Ferré P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J. 2002; 366(Pt 2):377–91.

16. Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 2005; 87:81–6.

17. Iizuka K, Horikawa Y. ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J. 2008; 55:617–24.

18. Kershaw EE, Hamm JK, Verhagen LA, Peroni O, Katic M, Flier JS. Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes. 2006; 55:148–57.

19. Zhai W, Xu C, Ling Y, Liu S, Deng J, Qi Y, Londos C, Xu G. Increased lipolysis in adipose tissues is associated with elevation of systemic free fatty acids and insulin resistance in perilipin null mice. Horm Metab Res. 2010; 42:247–53.

20. Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, Monks BR, Birnbaum MJ. Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol. 2010; 30:5009–20.

21. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010; 52:774–88.

22. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007; 56:16–23.

23. Zeyda M, Stulnig TM. Adipose tissue macrophages. Immunol Lett. 2007; 112:61–7.

24. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003; 300:1140–2.

25. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006; 55(Suppl 2):S9–S15.

26. Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005; 87:99–109.

27. Schmitz-Peiffer C, Whitehead JP. IRS-1 regulation in health and disease. IUBMB Life. 2003; 55:367–74.

28. Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008; 9:367–77.

29. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012; 142:711–725.e6.

30. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003; 112:91–100.

31. Lomonaco R, Sunny NE, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs. 2013; 73:1–14.

32. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005; 46:2347–55.

33. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011; 121:2111–7.

34. Olefsky JM, Saltiel AR. PPAR gamma and the treatment of insulin resistance. Trends Endocrinol Metab. 2000; 11:362–8.

35. Enomoto N, Takei Y, Yamashima S, Ikejima K, Kitamura T, Sato N. Protective effect of pioglitazone against endotoxin-induced liver injury through prevention of Kupffer cell sensitization. Alcohol Clin Exp Res. 2005; 29(12 Suppl):216S–9S.

36. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998; 114:842–5.

37. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008; 28:370–9.

38. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV Sr, Hevener AL, Farese RV Jr. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007; 6:69–78.

39. Garbarino J, Sturley SL. Saturated with fat: new perspectives on lipotoxicity. Curr Opin Clin Nutr Metab Care. 2009; 12:110–6.

40. Cusi K. Role of insulin resistance and lipotoxicity in nonalcoholic steatohepatitis. Clin Liver Dis. 2009; 13:545–63.

41. Fessler MB, Rudel LL, Brown JM. Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol. 2009; 20:379–85.

42. Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009; 50:1094–104.

43. Li Z, Berk M, McIntyre TM, Gores GJ, Feldstein AE. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology. 2008; 47:1495–503.

44. Novgorodov SA, Szulc ZM, Luberto C, Jones JA, Bielawski J, Bielawska A, Hannun YA, Obeid LM. Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J Biol Chem. 2005; 280:16096–105.

45. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab. 2006; 291:E275–81.

46. Listenberger LL, Ory DS, Schaffer JE. Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J Biol Chem. 2001; 276:14890–5.

47. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest. 2008; 118:2992–3002.

48. Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007; 46:1081–90.

49. Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 2008; 7:520–32.

50. Birkenfeld AL, Lee HY, Majumdar S, Jurczak MJ, Camporez JP, Jornayvaz FR, Frederick DW, Guigni B, Kahn M, Zhang D, Weismann D, Arafat AM, Pfeiffer AF, Lieske S, Oyadomari S, Ron D, Samuel VT, Shulman GI. Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism. J Biol Chem. 2011; 286:36163–70.