Abstract

Mini Review

Non-alcoholic fatty liver disease: Update on treatment options and translational implications of sleep disruption

Steve M D’Souza, Byung S Yoo, Kevin V Houston, Ankit J Patel, Parth J Parekh and David A Johnson*

Published: 17 August, 2021 | Volume 5 - Issue 1 | Pages: 032-038

Non-alcoholic fatty liver disease (NAFLD) is a condition that is associated with cirrhosis and hepatocellular carcinoma, and is increasing in prevalence worldwide. Sleep disruptions are commonly seen in NAFLD, and the disease process is associated with sleep disorders, including obstructive sleep apnea, circadian rhythm disorders, and insufficient sleep. The intermittent hypoxia seen in obstructive sleep apnea may contribute to fibrotic changes in the liver.
A major component of this linkage may be related to gut microbiome changes. One notable change is increase in Bacteroidetes/Firmicutes ratio, and decrease in flora that ferment fiber into anti-inflammatory short-chain fatty acids. Several therapeutic options exist for NAFLD that target both sleep and NAFLD, including non-pharmacological factors, such as lifestyle modification (mainly diet and exercise). Pharmacological options include melatonin, Vitamin E, thiazolidinediones, and fecal microbiota transplantation.
Core tip
The pathogenesis of non-alcoholic fatty liver disease is closely tied to sleep and circadian rhythm abnormalities, through shared inflammatory pathways and altered metabolism. This review explores the pathogenesis of NAFLD in the context of sleep and circadian abnormalities. The associated inflammatory response is linked to changes in gut-microbiome interactions that contribute to the disease process. Understanding of this linkage has implications for various therapies for disease mitigation.

Read Full Article HTML DOI: 10.29328/journal.acgh.1001030 Cite this Article Read Full Article PDF

Keywords:

Non-alcoholic fatty liver disease; Sleep; Circadian rhythms; Dysbiosis; Microbiome

References

  1. Vernon G, Baranova A, Younossi ZM. Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011; 34: 274-285. PubMed: https://pubmed.ncbi.nlm.nih.gov/21623852/
  2. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67: 328-357. PubMed: https://pubmed.ncbi.nlm.nih.gov/28714183/
  3. Loomba R, Wong R, Fraysse J, Shreay S, Li S, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020; 51: 1149-1159. PubMed: https://pubmed.ncbi.nlm.nih.gov/32372515/
  4. Chen K, Ma J, Jia X, Ai W, Ma Z, et al. Advancing the understanding of NAFLD to hepatocellular carcinoma development: From experimental models to humans. Biochim Biophys Acta - Rev Cancer. 2019; 1871: 117-125. PubMed: https://pubmed.ncbi.nlm.nih.gov/30528647/
  5. Diehl AM, Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med. 2017; 377: 2063-2072. PubMed: https://pubmed.ncbi.nlm.nih.gov/29166236/
  6. Angulo P. Nonalcoholic Fatty Liver Disease. N Engl J Med. 2002; 346: 1221-1231. PubMed: https://pubmed.ncbi.nlm.nih.gov/11961152/
  7. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology. 2006; 43: S99-S112. PubMed: https://pubmed.ncbi.nlm.nih.gov/16447287/
  8. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004; 114: 147-152. PubMed: https://pubmed.ncbi.nlm.nih.gov/15254578/
  9. Morris CJ, Yang JN, Garcia JI, Myers S, Bozzi I, et al. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. Proc Natl Acad Sci U S A. 2015; 112: E2225-E2234. PubMed: https://pubmed.ncbi.nlm.nih.gov/25870289/
  10. Eckel RH, Depner CM, Perreault L, Markwald RR, Smith MR, et al. Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity. Curr Biol. 2015; 25: 3004-3010. PubMed: https://pubmed.ncbi.nlm.nih.gov/26549253/
  11. Carmo-Silva S, Cavadas C. Hypothalamic dysfunction in obesity and metabolic disorders. In: Advances in Neurobiology. Springer New York LLC. 2017; 19: 73-116. PubMed: https://pubmed.ncbi.nlm.nih.gov/28933062/
  12. Tarquini R, Mazzoccoli G. Clock Genes, Metabolism, and Cardiovascular Risk. Heart Fail Clin. 2017; 13: 645-655. PubMed: https://pubmed.ncbi.nlm.nih.gov/28865774/
  13. Marcheva B, Ramsey KM, Peek CB, Affinati A, Maury E, et al. Circadian clocks and metabolism. Handb Exp Pharmacol. 2013; 217: 127-155. PubMed: https://pubmed.ncbi.nlm.nih.gov/23604478/
  14. Panda S. Circadian physiology of metabolism. Science. 2016; 354: 1008-1015. PubMed: https://pubmed.ncbi.nlm.nih.gov/27885007/
  15. Poggiogalle E, Jamshed H, Peterson CM. Circadian regulation of glucose, lipid, and energy metabolism in humans. Metabolism. 2018; 84: 11-27. PubMed: https://pubmed.ncbi.nlm.nih.gov/29195759/
  16. Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature. 2012; 485: 62-68. PubMed: https://pubmed.ncbi.nlm.nih.gov/22460951/
  17. Cho H, Zhao X, Hatori M, et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature. 2012; 485: 123-127. PubMed: https://pubmed.ncbi.nlm.nih.gov/22460952/
  18. Qaseem A, Dallas P, Owens DK, Starkey M, Holty J-EC, Shekelle P. Diagnosis of Obstructive Sleep Apnea in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2014; 161: 210-220. PubMed: https://pubmed.ncbi.nlm.nih.gov/25089864/
  19. Jin S, Jiang S, Hu A. Association between obstructive sleep apnea and non-alcoholic fatty liver disease: a systematic review and meta-analysis. Sleep Breath. 2018; 22: 841-851. PubMed: https://pubmed.ncbi.nlm.nih.gov/29335916/
  20. Lin QC, Chen L Da, Chen GP, et al. Association between nocturnal hypoxia and liver injury in the setting of nonalcoholic fatty liver disease. Sleep Breath. 2015; 19: 273-280. PubMed: https://pubmed.ncbi.nlm.nih.gov/24870112/
  21. Aron-Wisnewsky J, Minville C, Tordjman J, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol. 2012; 56: 225-233. PubMed: https://pubmed.ncbi.nlm.nih.gov/21703181/
  22. Musso G, Olivetti C, Cassader M, Gambino R. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: Emerging evidence and mechanisms. Semin Liver Dis. 2012; 32: 49-64. PubMed: https://pubmed.ncbi.nlm.nih.gov/22418888/
  23. Mesarwi OA, Shin M-K, Bevans-Fonti S, Schlesinger C, Shaw J, Polotsky VY. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease. Avila MA, ed. PLoS One. 2016; 11: e0168572. PubMed: https://pubmed.ncbi.nlm.nih.gov/28030556/
  24. Moon JOK, Welch TP, Gonzalez FJ, Copple BL. Reduced liver fibrosis in hypoxia-inducible factor-1α-deficient mice. Am J Physiol - Gastrointest Liver Physiol. 2009; 296: G582-592. PubMed: https://pubmed.ncbi.nlm.nih.gov/19136383/
  25. Akinnusi ME, Laporta R, El-Solh AA. Lectin-like oxidized low-density lipoprotein receptor-1 modulates endothelial apoptosis in obstructive sleep apnea. Chest. 2011; 140: 1503-1510. PubMed: https://pubmed.ncbi.nlm.nih.gov/21565964/
  26. Kim CW, Yun KE, Jung HS, Chang Y, Choi ES, et al. Sleep duration and quality in relation to non-alcoholic fatty liver disease in middle-aged workers and their spouses. J Hepatol. 2013; 59: 351-357. PubMed: https://pubmed.ncbi.nlm.nih.gov/23578884/
  27. Miyake T, Kumagi T, Furukawa S, Hirooka M, Kawasaki K, et al. Short sleep duration reduces the risk of nonalcoholic fatty liver disease onset in men: a community-based longitudinal cohort study. J Gastroenterol. 2015; 50: 583-589. PubMed: https://pubmed.ncbi.nlm.nih.gov/25120172/
  28. Liu C, Zhong R, Lou J, Pan A, Tang Y, et al. Nighttime sleep duration and risk of nonalcoholic fatty liver disease: the Dongfeng-Tongji prospective study. Ann Med. 2016; 48: 468-476. PubMed: https://pubmed.ncbi.nlm.nih.gov/27327959/
  29. Weng Z, Ou W, Huang J, Singh M, Wang M, et al. Circadian misalignment rather than sleep duration is associated with mafld: A population-based propensity score-matched study. Nat Sci Sleep. 2021; 13: 103-111. PubMed: https://pubmed.ncbi.nlm.nih.gov/33542668/
  30. Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH . EMBO Mol Med. 2019; 11: PubMed: https://pubmed.ncbi.nlm.nih.gov/30591521/
  31. Macpherson AJ, Heikenwalder M, Ganal-Vonarburg SC. The Liver at the Nexus of Host-Microbial Interactions. Cell Host Microbe. 2016; 20: 561-571. PubMed: https://pubmed.ncbi.nlm.nih.gov/27832587/
  32. Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci. 2019; 76: 1541-1558. PubMed: https://pubmed.ncbi.nlm.nih.gov/30683985/
  33. Milosevic I, Vujovic A, Barac A, Djelic M, Korac M, et al. Gut-liver axis, gut microbiota, and its modulation in the management of liver diseases: A review of the literature. Int J Mol Sci. 2019; 20: PubMed: https://pubmed.ncbi.nlm.nih.gov/30658519/
  34. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology. 2013; 57: 601-609. PubMed: https://pubmed.ncbi.nlm.nih.gov/23055155/
  35. Wang B, Jiang X, Cao M, et al. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci Rep. 2016; 6: 1-11.
  36. Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020; 17: 279-297. PubMed: https://pubmed.ncbi.nlm.nih.gov/32152478/
  37. Boursier J, Mueller O, Barret M, Machado M, Fizanne L, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016; 63: 764-775. PubMed: https://pubmed.ncbi.nlm.nih.gov/26600078/
  38. Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol. 2016; 13: 412-425. PubMed: https://pubmed.ncbi.nlm.nih.gov/27273168/
  39. Moreno-Indias I, Torres M, Montserrat JM, Sanchez-Alcoholado L, Cardona F, et al. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur Respir J. 2015; 45: 1055-1065. PubMed: https://pubmed.ncbi.nlm.nih.gov/25537565/
  40. Polyzos SA, Kang ES, Boutari C, Rhee EJ, Mantzoros CS. Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metabolism. 2020; 111: PubMed: https://pubmed.ncbi.nlm.nih.gov/32151660/
  41. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012; 55: 2005-2023. PubMed: https://pubmed.ncbi.nlm.nih.gov/22488764/
  42. Hannah WN, Harrison SA. Effect of Weight Loss, Diet, Exercise, and Bariatric Surgery on Nonalcoholic Fatty Liver Disease. Clin Liver Dis. 2016; 20: 339-350. PubMed: https://pubmed.ncbi.nlm.nih.gov/27063273/
  43. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas N, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015; 149: 367-378.e5. PubMed: https://pubmed.ncbi.nlm.nih.gov/25865049/
  44. Kouvari M, Boutari C, Chrysohoou C, Fragkopoulou E, Antonopoulou S, et al. Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: Results from the ATTICA prospective cohort study. Clin Nutr. 2021; 40: 3314-3324. PubMed: https://pubmed.ncbi.nlm.nih.gov/33234342/
  45. Borjigin J, Samantha Zhang L, Calinescu AA. Circadian regulation of pineal gland rhythmicity. Mol Cell Endocrinol. 2012; 349: 13-19. PubMed: https://pubmed.ncbi.nlm.nih.gov/21782887/
  46. Gao J, Xu K, Liu H, Liu G, Bai M, et al. Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Front Cell Infect Microbiol. 2018; 8: 13. PubMed: https://pubmed.ncbi.nlm.nih.gov/29468141/
  47. Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol An Off J Polish Physiol Soc. 2007; 58 Suppl 6: 97-103. PubMed: https://pubmed.ncbi.nlm.nih.gov/18212403/
  48. Miller SC, Pandi PSR, Esquifino AI, Cardinali DP, Maestroni GJM. The role of melatonin in immuno-enhancement: Potential application in cancer. Int J Exp Pathol. 2006; 87: 81-87. PubMed: https://pubmed.ncbi.nlm.nih.gov/16623752/
  49. Bonomini F, Dos Santos M, Veronese FV, Rezzani R. NLRP3 inflammasome modulation by melatonin supplementation in chronic pristane-induced lupus nephritis. Int J Mol Sci. 2019; 20: PubMed: https://pubmed.ncbi.nlm.nih.gov/31311094/
  50. Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, et al. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 2019; 10: 317. PubMed: https://pubmed.ncbi.nlm.nih.gov/30962427/
  51. Galano A, Tan DX, Reiter RJ. Melatonin: A versatile protector against oxidative DNA damage. Molecules. 2018; 23: 530. PubMed: https://pubmed.ncbi.nlm.nih.gov/29495460/
  52. Zhou J, Zhang S, Zhao X, Wei T. Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid-β1-42. J Pineal Res. 2008; 45: 157-165. PubMed: https://pubmed.ncbi.nlm.nih.gov/18298462/
  53. Pakravan H, Ahmadian M, Fani A, Aghaee D, Brumanad S, et al. The Effects of Melatonin in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial. Adv Biomed Res. 2017; 6: 40. PubMed: https://pubmed.ncbi.nlm.nih.gov/28503495/
  54. Stacchiotti A, Grossi I, García-Gómez R, Patel GA, Salvi A, et al. Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy. Cells. 2019; 8: 1053. PubMed: https://pubmed.ncbi.nlm.nih.gov/31500354/
  55. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med. 2010; 362: 1675-1685. PubMed: https://pubmed.ncbi.nlm.nih.gov/20427778/
  56. Sumida Y, Naito Y, Tanaka S, Sakai K, Inada Y, et al. Long-term (≥2 yr) efficacy of vitamin E for non-alcoholic steatohepatitis. Hepatogastroenterology. 2013; 60: 1445-1450. PubMed: https://pubmed.ncbi.nlm.nih.gov/23933938/
  57. Rinella ME, Sanyal AJ. Management of NAFLD: A stage-based approach. Nat Rev Gastroenterol Hepatol. 2016; 13: 196-205. PubMed: https://pubmed.ncbi.nlm.nih.gov/26907882/
  58. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005; 142: 37-46. PubMed: https://pubmed.ncbi.nlm.nih.gov/15537682/
  59. Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: Meta-analysis of randomised controlled trials. BMJ. 2010; 341: c5702. PubMed: https://pubmed.ncbi.nlm.nih.gov/21051774/
  60. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The selenium and vitamin E cancer prevention trial (SELECT). JAMA - J Am Med Assoc. 2009; 301: 39-51. PubMed: https://pubmed.ncbi.nlm.nih.gov/19066370/
  61. Belfort R, Harrison SA, Brown K, Darland C, Finch J, et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. N Engl J Med. 2006; 355: 2297-2307. PubMed: https://pubmed.ncbi.nlm.nih.gov/17135584/
  62. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, et al. Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis. Gastroenterology. 2008; 135: 1176-1184. PubMed: https://pubmed.ncbi.nlm.nih.gov/18718471/
  63. Singh S, Khera R, Allen AM, Murad MH, Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015; 62: 1417-1432. PubMed: https://pubmed.ncbi.nlm.nih.gov/26189925/
  64. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus a randomized trial. Ann Intern Med. 2016; 165: 305-315. PubMed: https://pubmed.ncbi.nlm.nih.gov/27322798/
  65. Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, et al. Role of Vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: A randomized controlled trial. Diabetes Care. 2019; 42: 1481-1488. PubMed: https://pubmed.ncbi.nlm.nih.gov/31332029/
  66. Budd J, Cusi K. Role of Agents for the Treatment of Diabetes in the Management of Nonalcoholic Fatty Liver Disease. Curr Diab Rep. 2020; 20: 59. PubMed: https://pubmed.ncbi.nlm.nih.gov/33015726/
  67. Kumar J, Memon RS, Shahid I, Rizwan T, Zaman M, et al. Antidiabetic drugs and non-alcoholic fatty liver disease: A systematic review, meta-analysis and evidence map. Dig Liver Dis. 2021; 53: 44-51. PubMed: https://pubmed.ncbi.nlm.nih.gov/32912770/
  68. Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018; 53: 362-376. PubMed: https://pubmed.ncbi.nlm.nih.gov/29247356/
  69. Zhou D, Pan Q, Shen F, Cao HX, Ding WJ, et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep. 2017; 7: 1529. PubMed: https://pubmed.ncbi.nlm.nih.gov/28484247/
  70. Craven L, Rahman A, Nair Parvathy S, Beaton M, Silverman J, et al. Allogenic Fecal Microbiota Transplantation in Patients with Nonalcoholic Fatty Liver Disease Improves Abnormal Small Intestinal Permeability: A Randomized Control Trial. Am J Gastroenterol. 2020; 115: 1055-1065. PubMed: https://pubmed.ncbi.nlm.nih.gov/32618656/
  71. Citi S. Intestinal barriers protect against disease: Leaky cell-cell junctions contribute to inflammatory and autoimmune diseases. Science. 2018; 359: 1097-1098. PubMed: https://pubmed.ncbi.nlm.nih.gov/29590026/

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