Skip to main content
SpringerLink
Log in

Function of Autophagy in Nonalcoholic Fatty Liver Disease

  • Review Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Autophagy is a lysosomal degradative pathway that functions to promote cell survival by supplying energy in times of stress or by removing damaged organelles and proteins after injury. The involvement of autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) was first suggested by the finding that this pathway mediates the breakdown of intracellular lipids in hepatocytes and therefore may regulate the development of hepatic steatosis. Subsequent studies have demonstrated additional critical functions for autophagy in hepatocytes and other hepatic cell types such as macrophages and stellate cells that regulate insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. These findings suggest a number of possible mechanistic roles for autophagy in the development of NAFLD and progression to NASH and its complications. The functions of autophagy in the liver, together with findings of decreased hepatic autophagy in association with conditions that predispose to NAFLD such as obesity and aging, suggest that autophagy may be a novel therapeutic target in this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CMA:

Chaperone-mediated autophagy

FFA:

Free fatty acid

HCC:

Hepatocellular carcinoma

HFD:

High-fat diet

FIP200:

Focal adhesion family kinase-interacting protein of 200 kDa

JNK:

c-Jun N-terminal kinase

LAMP-2A:

Lysosome-associated membrane protein type 2A

LC3:

Microtubule-associated protein light chain 3

LPS:

Lipopolysaccharide

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

TFEB:

Transcription factor EB

TG:

Triglyceride

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

References

  1. Mehrpour M, Esclatine A, Beau I, Codogno P. Autophagy in health and disease. 1. Regulation and significance of autophagy: an overview. Am J Physiol Cell Physiol. 2010;298:C776–C785.

    Article  CAS  PubMed  Google Scholar 

  2. Orenstein SJ, Cuervo AM. Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol. 2010;21:719–726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880–884.

    Article  CAS  PubMed  Google Scholar 

  4. Finn PF, Dice JF. Proteolytic and lipolytic responses to starvation. Nutrition. 2006;22:830–844.

    Article  CAS  PubMed  Google Scholar 

  5. Iwata J, Ezaki J, Komatsu M, et al. Excess peroxisomes are degraded by autophagic machinery in mammals. J Biol Chem. 2006;281:4035–4041.

    Article  CAS  PubMed  Google Scholar 

  6. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462:245–253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fontana L, Zhao E, Amir M, Dong H, Tanaka K, Czaja MJ. Aging promotes the development of diet-induced murine steatohepatitis but not steatosis. Hepatology. 2013;57:995–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Noureddin M, Yates KP, Vaughn IA, et al. Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. Hepatology. 2013;58:1644–1654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–1135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11:467–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rodriguez-Navarro JA, Kaushik S, Koga H, et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc Natl Acad Sci USA. 2012;109:E705–E714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fukuo Y, Yamashina S, Sonoue H, et al. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res. 2014;44:1026–1036.

    Article  CAS  PubMed  Google Scholar 

  13. Gonzalez-Rodriguez A, Mayoral R, Agra N, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014;5:e1179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kashima J, Shintani-Ishida K, Nakajima M, et al. Immunohistochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in normal and steatotic human livers. Hepatol Res. 2014;44:779–787.

    Article  CAS  PubMed  Google Scholar 

  15. Jansen HJ, van Essen P, Koenen T, et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology. 2012;153:5866–5874.

    Article  CAS  PubMed  Google Scholar 

  16. Kovsan J, Bluher M, Tarnovscki T, et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab. 2011;96:E268–E277.

    Article  CAS  PubMed  Google Scholar 

  17. Czaja MJ. Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology. 2011;140:1895–1908.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Koga H, Kaushik S, Cuervo AM. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 2010;24:3052–3065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Park HW, Park H, Semple IA, et al. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat Commun. 2014;5:4834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu HY, Han J, Cao SY, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009;284:31484–31492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:351–359.

    Article  CAS  PubMed  Google Scholar 

  22. Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:545–563.

    Article  PubMed  Google Scholar 

  23. Day CP, James OF. Steatohepatitis: A tale of two “hits”? Gastroenterology. 1998;114:842–845.

    Article  CAS  PubMed  Google Scholar 

  24. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lalor PF, Faint J, Aarbodem Y, Hubscher SG, Adams DH. The role of cytokines and chemokines in the development of steatohepatitis. Semin Liver Dis. 2007;27:173–193.

    Article  CAS  PubMed  Google Scholar 

  26. Czaja MJ. Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications. Am J Physiol Cell Physiol. 2010;298:C973–C978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ding WX, Li M, Chen X, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010;139:1740–1752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pan M, Maitin V, Parathath S, et al. Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: a pathway for late-stage quality control. Proc Natl Acad Sci USA. 2008;105:5862–5867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xiong X, Tao R, DePinho RA, Dong XC. The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism. J Biol Chem. 2012;287:39107–39114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Settembre C, De Cegli R, Mansueto G, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol. 2013;15:647–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim KH, Jeong YT, Oh H, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013;19:83–92.

    Article  CAS  PubMed  Google Scholar 

  32. Ma D, Molusky MM, Song J, et al. Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD. Mol Endocrinol. 2013;27:1643–1654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schneider JL, Suh Y, Cuervo AM. Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. Cell Metab. 2014;20:417–432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kaushik S, Cuervo AM. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol. 2015;17:759–770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1497–1502.

    Article  CAS  PubMed  Google Scholar 

  36. Yousefi S, Perozzo R, Schmid I, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol. 2006;8:1124–1132.

    Article  CAS  PubMed  Google Scholar 

  37. Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122:927–939.

    Article  CAS  PubMed  Google Scholar 

  38. Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31:430–434.

    Article  CAS  PubMed  Google Scholar 

  39. Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005;8:3–5.

    Article  CAS  PubMed  Google Scholar 

  40. Wang Y, Singh R, Xiang Y, Czaja MJ. Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress. Hepatology. 2010;52:266–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology. 2009;49:87–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6:998–1003.

    Article  CAS  PubMed  Google Scholar 

  43. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol. 2003;39:978–983.

    Article  CAS  PubMed  Google Scholar 

  44. Wang Y, Singh R, Massey AC, et al. Loss of macroautophagy promotes or prevents fibroblast apoptosis depending on the death stimulus. J Biol Chem. 2008;283:4766–4777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Amir M, Zhao E, Fontana L, et al. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ. 2013;20:878–887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26:9220–9231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Maher JJ, Leon P, Ryan JC. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology. 2008;48:670–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Saitoh T, Akira S. Regulation of innate immune responses by autophagy-related proteins. J Cell Biol. 2010;189:925–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature. 2008;456:264–268.

    Article  CAS  PubMed  Google Scholar 

  50. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47:571–579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G518–G525.

    Article  CAS  PubMed  Google Scholar 

  52. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007;27:135–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu K, Zhao E, Ilyas G, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy. 2015;11:271–284.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ilyas G, Zhao E, Liu K, et al. Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1beta. J Hepatol. 2016;64:118–127.

    Article  CAS  PubMed  Google Scholar 

  55. Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology. 2012;142:938–946.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Thoen LF, Guimaraes EL, Dolle L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol. 2011;55:1353–1360.

    Article  CAS  PubMed  Google Scholar 

  57. Lodder J, Denaes T, Chobert MN, et al. Macrophage autophagy protects against liver fibrosis in mice. Autophagy. 2015;11:1280–1292.

    Article  CAS  PubMed  Google Scholar 

  58. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.

    Article  PubMed  Google Scholar 

  59. White E. The role for autophagy in cancer. J Clin Invest. 2015;125:42–46.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112:1809–1820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA. 2003;100:15077–15082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ding ZB, Shi YH, Zhou J, et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 2008;68:9167–9175.

    Article  CAS  PubMed  Google Scholar 

  63. Takamura A, Komatsu M, Hara T, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25:795–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Inami Y, Waguri S, Sakamoto A, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193:275–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ni HM, Woolbright BL, Williams J, et al. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol. 2014;61:617–625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. He C, Bassik MC, Moresi V, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481:511–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012;55:429–436.

    Article  CAS  PubMed  Google Scholar 

  68. Sinha RA, Farah BL, Singh BK, et al. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology. 2014;59:1366–1380.

    Article  CAS  PubMed  Google Scholar 

  69. Sinha RA, You SH, Zhou J, et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 2012;122:2428–2438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol. 2003;37:340–343.

    Article  PubMed  Google Scholar 

  71. Barchetta I, Angelico F, Del Ben M, et al. Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes. BMC Med. 2011;9:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Campbell GR, Spector SA. Hormonally active vitamin D3 (1α,25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection. J Biol Chem. 2011;286:18890–18902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hidvegi T, Ewing M, Hale P, et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010;329:229–232.

    Article  CAS  PubMed  Google Scholar 

  74. Lin CW, Zhang H, Li M, et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol. 2013;58:993–999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE. 2011;6:e25269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Supported by NIH Grants R01DK061498 and R01AA022601.

Author information

Authors and Affiliations

  1. Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, 615 Michael Street, Suite 201, Atlanta, GA, 30322, USA

    Mark J. Czaja

Authors
  1. Mark J. Czaja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark J. Czaja.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Czaja, M.J. Function of Autophagy in Nonalcoholic Fatty Liver Disease. Dig Dis Sci 61, 1304–1313 (2016). https://doi.org/10.1007/s10620-015-4025-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-015-4025-x

Keywords

Search

Navigation