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__NOTOC__
__NOTOC__
{{Non alcoholic fatty liver disease}}
{{Non alcoholic fatty liver disease}}
{{CMG}}; {{AE}} {{VKG}}
{{CMG}}; {{AE}} {{MKK}}


==Overview==
==Overview==
The exact pathogenesis of NAFLD is not fully understood, but is believed due to interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be best explained by 2 hit hypothesis. The first hit is [[steatosis]]. The second hit is controversial and is likely cause changes that leads from [[hepatic steatosis]] to [[hepatic]] [[inflammation]] and [[fibrosis]] by way of [[lipid peroxidation]].
The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be best explained by 2 hit hypothesis. The first hit is [[steatosis]]. The second hit is controversial and is likely cause changes that leads from [[hepatic steatosis]] to [[hepatic]] [[inflammation]] and [[fibrosis]] by way of [[lipid peroxidation]].


==Pathophysiology==
==Pathophysiology==
The exact pathogenesis of NAFLD is not fully understood, but is believed due to interaction of multiple factors.
The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors.


=== <u>2 hit hypothesis</u> ===
=== <u>2 hit hypothesis</u> ===
Line 21: Line 21:


=== Free fatty acids ===
=== Free fatty acids ===
* [[Free fatty acids]] (FFA) play very crucial role in damaging the liver indirectly by either undergoing [[β-oxidation]] or are esterified with [[glycerol]] to form [[triglycerides]], leading to hepatic fat accumulation.
* [[Free fatty acids]] (FFA) play very crucial role in damaging the liver indirectly by either undergoing [[β-oxidation]] or are esterified with [[glycerol]] to form [[triglycerides]], leading to hepatic fat accumulation.<ref name="pmid27973438">{{cite journal |vauthors=Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F |title=Pathophysiology of Non Alcoholic Fatty Liver Disease |journal=Int J Mol Sci |volume=17 |issue=12 |pages= |year=2016 |pmid=27973438 |pmc=5187882 |doi=10.3390/ijms17122082 |url=}}</ref><ref name="pmid18317565">{{cite journal |vauthors=Postic C, Girard J |title=Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice |journal=J. Clin. Invest. |volume=118 |issue=3 |pages=829–38 |year=2008 |pmid=18317565 |pmc=2254980 |doi=10.1172/JCI34275 |url=}}</ref><ref name="pmid18956293">{{cite journal |vauthors=Jou J, Choi SS, Diehl AM |title=Mechanisms of disease progression in nonalcoholic fatty liver disease |journal=Semin. Liver Dis. |volume=28 |issue=4 |pages=370–9 |year=2008 |pmid=18956293 |doi=10.1055/s-0028-1091981 |url=}}</ref>
* By [[Upregulation|upregulating]] [[TNF-alpha]] expression via [[Lysosomal enzymes|lysosomal]] pathway, [[free fatty acids]] make the [[liver]] susceptible to [[oxidative stress]].<ref name="pmid15239102">{{cite journal |vauthors=Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ |title=Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway |journal=Hepatology |volume=40 |issue=1 |pages=185–94 |year=2004 |pmid=15239102 |doi=10.1002/hep.20283 |url=}}</ref>
* By [[Upregulation|upregulating]] [[TNF-alpha]] expression via [[Lysosomal enzymes|lysosomal]] pathway, [[free fatty acids]] make the [[liver]] susceptible to [[oxidative stress]].<ref name="pmid15239102">{{cite journal |vauthors=Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ |title=Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway |journal=Hepatology |volume=40 |issue=1 |pages=185–94 |year=2004 |pmid=15239102 |doi=10.1002/hep.20283 |url=}}</ref>


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* Progenitor cells along with hepatocyte-like cells are responsible for [[fibrosis]] and [[carcinogenesis]] in non alcoholic fatty liver.<ref name="pmid19914930">{{cite journal |vauthors=Dowman JK, Tomlinson JW, Newsome PN |title=Pathogenesis of non-alcoholic fatty liver disease |journal=QJM |volume=103 |issue=2 |pages=71–83 |year=2010 |pmid=19914930 |pmc=2810391 |doi=10.1093/qjmed/hcp158 |url=}}</ref>  
* Progenitor cells along with hepatocyte-like cells are responsible for [[fibrosis]] and [[carcinogenesis]] in non alcoholic fatty liver.<ref name="pmid19914930">{{cite journal |vauthors=Dowman JK, Tomlinson JW, Newsome PN |title=Pathogenesis of non-alcoholic fatty liver disease |journal=QJM |volume=103 |issue=2 |pages=71–83 |year=2010 |pmid=19914930 |pmc=2810391 |doi=10.1093/qjmed/hcp158 |url=}}</ref>  


===Endotoxins===
===Endotoxins<ref name="pmid20353583">{{cite journal |vauthors=Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG |title=Elevated endotoxin levels in non-alcoholic fatty liver disease |journal=J Inflamm (Lond) |volume=7 |issue= |pages=15 |year=2010 |pmid=20353583 |pmc=2873499 |doi=10.1186/1476-9255-7-15 |url=}}</ref><ref name="pmid24426189">{{cite journal |vauthors=Fukunishi S, Sujishi T, Takeshita A, Ohama H, Tsuchimoto Y, Asai A, Tsuda Y, Higuchi K |title=Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats |journal=J Clin Biochem Nutr |volume=54 |issue=1 |pages=39–44 |year=2014 |pmid=24426189 |pmc=3882483 |doi=10.3164/jcbn.13-49 |url=}}</ref><ref name="pmid203535832">{{cite journal |vauthors=Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG |title=Elevated endotoxin levels in non-alcoholic fatty liver disease |journal=J Inflamm (Lond) |volume=7 |issue= |pages=15 |year=2010 |pmid=20353583 |pmc=2873499 |doi=10.1186/1476-9255-7-15 |url=}}</ref>===
* [[Obese]] patients who underwent [[Jejuno-ileal bypass|jejuno-ileal bypass surgery]] has the risk of developing [[bacterial endotoxins]] in the [[portal circulation]] due to [[Small intestine|small intestinal deformity]].<ref>Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999</ref>
* [[Obese]] patients who underwent [[Jejuno-ileal bypass|jejuno-ileal bypass surgery]] has the risk of developing [[bacterial endotoxins]] in the [[portal circulation]] due to [[Small intestine|small intestinal deformity]].  
* Increase in [[small bowel bacterial overgrowth]] due to decreased gastric motility.   
* Increase in [[small bowel bacterial overgrowth]] due to decreased gastric motility.   
* Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory [[cytokines]], such as [[tumor necrosis factor-alpha]].  
* Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory [[cytokines]], such as [[tumor necrosis factor-alpha]].  
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===Adiponectin===
===Adiponectin===
* [[Adiponectin]] is an anti-atherogenic, [[insulin]] sensitizing [[cytokine]] whose [[secretion]] is decreased in [[obesity]].
* [[Adiponectin]] is an anti-atherogenic, [[insulin]] sensitizing [[cytokine]] whose [[secretion]] is decreased in [[obesity]].<ref name="pmid18460922">{{cite journal |vauthors=Choi SS, Diehl AM |title=Hepatic triglyceride synthesis and nonalcoholic fatty liver disease |journal=Curr. Opin. Lipidol. |volume=19 |issue=3 |pages=295–300 |year=2008 |pmid=18460922 |doi=10.1097/MOL.0b013e3282ff5e55 |url=}}</ref><ref name="pmid20415685">{{cite journal |vauthors=Polyzos SA, Kountouras J, Zavos C, Tsiaousi E |title=The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease |journal=Diabetes Obes Metab |volume=12 |issue=5 |pages=365–83 |year=2010 |pmid=20415685 |doi=10.1111/j.1463-1326.2009.01176.x |url=}}</ref><ref name="pmid19355912">{{cite journal |vauthors=Polyzos SA, Kountouras J, Zavos C |title=Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines |journal=Curr. Mol. Med. |volume=9 |issue=3 |pages=299–314 |year=2009 |pmid=19355912 |doi= |url=}}</ref><ref name="pmid23430039">{{cite journal |vauthors=Finelli C, Tarantino G |title=What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? |journal=World J. Gastroenterol. |volume=19 |issue=6 |pages=802–12 |year=2013 |pmid=23430039 |pmc=3574877 |doi=10.3748/wjg.v19.i6.802 |url=}}</ref>
* There is an inverse relationship between circulating concentrations of [[adiponectin]] and [[tumor necrosis factor]].<ref name="urlAdiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice | Diabetes">{{cite web |url=http://diabetes.diabetesjournals.org/content/56/8/1969 |title=Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice &#124; Diabetes |format= |work= |accessdate=}}</ref>
* There is an inverse relationship between circulating concentrations of [[adiponectin]] and [[tumor necrosis factor]].
* Any conditions that cause low production of [[adiponectin]] ( consuming high amounts of [[Polyunsaturated fatty acids|poly unsaturated fatty acids]]) results in production of [[TNF alpha]].<ref name="urlThe Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background">{{cite web |url=https://www.hindawi.com/journals/grp/2016/2862173/ |title=The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background |format= |work= |accessdate=}}</ref>
* Any conditions that cause low production of [[adiponectin]] ( consuming high amounts of [[Polyunsaturated fatty acids|poly unsaturated fatty acids]]) results in production of [[TNF alpha]].  


===Adenosine===
===Adenosine<ref name="pmid20395005">{{cite journal |vauthors=Robson SC, Schuppan D |title=Adenosine: tipping the balance towards hepatic steatosis and fibrosis |journal=J. Hepatol. |volume=52 |issue=6 |pages=941–3 |year=2010 |pmid=20395005 |pmc=2875264 |doi=10.1016/j.jhep.2010.02.009 |url=}}</ref>===
* Alteration of  [[purinergic metabolism]] is another important pathway responsible for development of non-alcoholic liver disease.  
* Alteration of  [[purinergic metabolism]] is another important pathway responsible for development of non-alcoholic liver disease.  
* [[Adenosine]] receptor A2A is a major factor in the pathogenesis of [[cirrhosis]].<ref name="Chan" />
* [[Adenosine]] receptor A2A is a major factor in the pathogenesis of [[cirrhosis]].  
* CD39 is the dominant vascular  [[ectonucleotidase]] in the [[liver]] that hydrolyzes [[extracellular]] [[ATP]] and [[ADP]] to [[Adenosine monophosphate|AMP]] which can then be converted to [[adenosine]] via [[Ectonucleotidase|ecto-5’-nucleotidase]]/CD73.  
* CD39 is the dominant vascular  [[ectonucleotidase]] in the [[liver]] that hydrolyzes [[extracellular]] [[ATP]] and [[ADP]] to [[Adenosine monophosphate|AMP]] which can then be converted to [[adenosine]] via [[Ectonucleotidase|ecto-5’-nucleotidase]]/CD73.<ref name="pmid18567823">{{cite journal |vauthors=Enjyoji K, Kotani K, Thukral C, Blumel B, Sun X, Wu Y, Imai M, Friedman D, Csizmadia E, Bleibel W, Kahn BB, Robson SC |title=Deletion of cd39/entpd1 results in hepatic insulin resistance |journal=Diabetes |volume=57 |issue=9 |pages=2311–20 |year=2008 |pmid=18567823 |pmc=2518482 |doi=10.2337/db07-1265 |url=}}</ref>
* Alterations in [[Purinergic metabolism|purinergic signaling]] induced by altered CD39 mutation have major impacts upon [[Hepatic metabolism, regulation, and excretion|hepatic metabolism]], repair mechanisms, regeneration and associated [[immune responses]].
* Alterations in [[Purinergic metabolism|purinergic signaling]] induced by altered CD39 mutation have major impacts upon [[Hepatic metabolism, regulation, and excretion|hepatic metabolism]], repair mechanisms, regeneration and associated [[immune responses]].
* [[Adenosine]] forms a supportive link in the cell’s cascade healing response to [[inflammation]].
* [[Adenosine]] forms a supportive link in the cell’s cascade healing response to [[inflammation]].
** [[Adenosine]] suppresses [[inflammation]] by enhancing [[fibrosis]].
** [[Adenosine]] suppresses [[inflammation]] by enhancing [[fibrosis]].
* CD39 deletion shifts the local population of [[cytokines]] to produce [[TNF alpha]].<ref>Kunzli BM et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230</ref><ref>Montesinos MC et al. Wound healing is accelerated by agonists of [[adenosine]] A2 (G alpha s-linked) receptors. J. Exp. Med.1997;186:1615–162010-11)</ref><ref name="Chan">Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, et al. [[adenosine]] A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 2006;148:1144-1155.</ref><ref>Kunzli BM et al. Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-null mice. Gastroenterology. 2008 January ; 134(1): 292–305. </ref>
* CD39 deletion shifts the local population of [[cytokines]] to produce [[TNF alpha]].


===Fibroblast Growth Factor 21===
===Fibroblast Growth Factor 21<ref name="pmid25516477">{{cite journal |vauthors=Liu J, Xu Y, Hu Y, Wang G |title=The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy |journal=Metab. Clin. Exp. |volume=64 |issue=3 |pages=380–90 |year=2015 |pmid=25516477 |doi=10.1016/j.metabol.2014.11.009 |url=}}</ref>===
* [[Fibroblast growth factor 21]] ([[FGF21]]) is an important metabolic regulator of [[glucose]] and [[lipid]] [[metabolism]].
* [[Fibroblast growth factor 21]] ([[FGF21]]) is an important metabolic regulator of [[glucose]] and [[lipid]] [[metabolism]].
* [[FGF21]] moderates or induces the [[hepatic]] response to a [[fasting]] state by [[gluconeogenesis]], [[fatty acid oxidation]], and [[ketogenesis]].<ref>Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S</ref>
* [[FGF21]] moderates or induces the [[hepatic]] response to a [[fasting]] state by [[gluconeogenesis]], [[fatty acid oxidation]], and [[ketogenesis]].  
* Moreover, it is a crucial component of the hepatic lipid [[oxidation]] machinery, as proliferator-activated receptor activation.<ref>Badman MK et all. Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARa and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States. Cell Metabolism 2007;5:426–437</ref>
* Moreover, it is a crucial component of the hepatic lipid [[oxidation]] machinery, as proliferator-activated receptor activation.  
* [[FGF21]] is responsible for normal [[blood glucose]], [[insulin]], and [[lipid]] levels in normal individuals.  
* [[FGF21]] is responsible for normal [[blood glucose]], [[insulin]], and [[lipid]] levels in normal individuals.  
* Low levels of FGF21 are closely associated with the [[obesity]], [[insulin resistance]], [[type two diabetes mellitus]] and [[hyperlipidemia]].<ref>Xu, J et al. Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice. Diabetes 58:250–259, 2009</ref><ref>Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S</ref><ref>Xu CF, Yu CH, Xu L, Sa XY, Li YM. Hypouricemic therapy: A novel potential therapeutic option for nonalcoholic fatty liver disease.Hepatology. 2010 Jun 11. [Epub ahead of print]</ref>
* Low levels of FGF21 are closely associated with the [[obesity]], [[insulin resistance]], [[type two diabetes mellitus]] and [[hyperlipidemia]].


== Associated Conditions ==
== Associated Conditions ==
* Most patients have associated features of the [[metabolic syndrome]] including [[obesity]], [[diabetes mellitus type 2]], [[hyperlipidemia]] ([[hypertriglyceridemia]]), and [[hypertension]]
* Most patients have associated features of the [[metabolic syndrome]] including [[obesity]], [[diabetes mellitus type 2]], [[hyperlipidemia]] ([[hypertriglyceridemia]]), and [[hypertension]]
* Patients may suffer from complications of obesity such as [[obstructive sleep apnea]] , orthopedic complications, and [[polycystic ovary syndrome]].<ref>Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.</ref>
* Patients may suffer from complications of obesity such as [[obstructive sleep apnea]] , orthopedic complications, and [[polycystic ovary syndrome]].


== Microscopic Pathology ==
== Microscopic Pathology ==
On microscopic histopathological analysis characteristic findings of non-alcoholic liver disease include:
On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:
* Macrovesicular [[steatosis]]
* Macrovesicular [[steatosis]]


* Predominant lobular inflammation in form of spotty [[necrosis]] in cases where [[steatosis]] is associated with [[inflammation]].
* Predominant lobular [[inflammation]] in form of spotty [[necrosis]] in cases where [[steatosis]] is associated with [[inflammation]].


* Ballooning degeneration (hallmark of [[steatohepatitis]])
* Ballooning [[degeneration]] (hallmark of [[steatohepatitis]])
** Characterized by cellular swelling, rarefaction of the hepatocytic [[cytoplasm]] and clumped strands of intermediate filaments.
** Characterized by cellular swelling, rarefaction of the hepatocytic [[cytoplasm]] and clumped strands of intermediate [[filaments]].
* [[Mallory bodies|Mallory-Denk bodies]] (MDB)
* [[Mallory bodies|Mallory-Denk bodies]] (MDB)
* [[Fibrosis]]  
* [[Fibrosis]]  
* Perivenular and pericellular (peri-sinusoidal) fibrosis.
* Perivenular and pericellular (peri-sinusoidal) [[fibrosis]].


==References==
==References==

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Overview

The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be best explained by 2 hit hypothesis. The first hit is steatosis. The second hit is controversial and is likely cause changes that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation.

Pathophysiology

The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors.

2 hit hypothesis

Pathogenesis of non-alcoholic liver disease can be summarized by 2 hit hypothesis. According to 2 hit hypothesis:

  • The first hit results in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.
  • On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.[1]

Free fatty acids

Endotoxins[6][7][8]

Adiponectin

Adenosine[13]

Fibroblast Growth Factor 21[15]

Associated Conditions

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:

References

  1. ↑ 1.0 1.1 Dowman JK, Tomlinson JW, Newsome PN (2010). "Pathogenesis of non-alcoholic fatty liver disease". QJM. 103 (2): 71–83. doi:10.1093/qjmed/hcp158. PMC 2810391. PMID 19914930.
  2. ↑ Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F (2016). "Pathophysiology of Non Alcoholic Fatty Liver Disease". Int J Mol Sci. 17 (12). doi:10.3390/ijms17122082. PMC 5187882. PMID 27973438.
  3. ↑ Postic C, Girard J (2008). "Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice". J. Clin. Invest. 118 (3): 829–38. doi:10.1172/JCI34275. PMC 2254980. PMID 18317565.
  4. ↑ Jou J, Choi SS, Diehl AM (2008). "Mechanisms of disease progression in nonalcoholic fatty liver disease". Semin. Liver Dis. 28 (4): 370–9. doi:10.1055/s-0028-1091981. PMID 18956293.
  5. ↑ Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004). "Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway". Hepatology. 40 (1): 185–94. doi:10.1002/hep.20283. PMID 15239102.
  6. ↑ Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG (2010). "Elevated endotoxin levels in non-alcoholic fatty liver disease". J Inflamm (Lond). 7: 15. doi:10.1186/1476-9255-7-15. PMC 2873499. PMID 20353583.
  7. ↑ Fukunishi S, Sujishi T, Takeshita A, Ohama H, Tsuchimoto Y, Asai A, Tsuda Y, Higuchi K (2014). "Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats". J Clin Biochem Nutr. 54 (1): 39–44. doi:10.3164/jcbn.13-49. PMC 3882483. PMID 24426189.
  8. ↑ Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG (2010). "Elevated endotoxin levels in non-alcoholic fatty liver disease". J Inflamm (Lond). 7: 15. doi:10.1186/1476-9255-7-15. PMC 2873499. PMID 20353583.
  9. ↑ Choi SS, Diehl AM (2008). "Hepatic triglyceride synthesis and nonalcoholic fatty liver disease". Curr. Opin. Lipidol. 19 (3): 295–300. doi:10.1097/MOL.0b013e3282ff5e55. PMID 18460922.
  10. ↑ Polyzos SA, Kountouras J, Zavos C, Tsiaousi E (2010). "The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease". Diabetes Obes Metab. 12 (5): 365–83. doi:10.1111/j.1463-1326.2009.01176.x. PMID 20415685.
  11. ↑ Polyzos SA, Kountouras J, Zavos C (2009). "Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines". Curr. Mol. Med. 9 (3): 299–314. PMID 19355912.
  12. ↑ Finelli C, Tarantino G (2013). "What is the role of adiponectin in obesity related non-alcoholic fatty liver disease?". World J. Gastroenterol. 19 (6): 802–12. doi:10.3748/wjg.v19.i6.802. PMC 3574877. PMID 23430039.
  13. ↑ Robson SC, Schuppan D (2010). "Adenosine: tipping the balance towards hepatic steatosis and fibrosis". J. Hepatol. 52 (6): 941–3. doi:10.1016/j.jhep.2010.02.009. PMC 2875264. PMID 20395005.
  14. ↑ Enjyoji K, Kotani K, Thukral C, Blumel B, Sun X, Wu Y, Imai M, Friedman D, Csizmadia E, Bleibel W, Kahn BB, Robson SC (2008). "Deletion of cd39/entpd1 results in hepatic insulin resistance". Diabetes. 57 (9): 2311–20. doi:10.2337/db07-1265. PMC 2518482. PMID 18567823.
  15. ↑ Liu J, Xu Y, Hu Y, Wang G (2015). "The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy". Metab. Clin. Exp. 64 (3): 380–90. doi:10.1016/j.metabol.2014.11.009. PMID 25516477.

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