Page 86 - EASL POSTGRADUATE COURSE
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dramatically, suggesting that in cases of NAFLD the adipose tissue is the major cytokine source. The
adipose tissue, however, is also a major source of ‘beneficial’, i.e. anti-inflammatory, adipocytokines such
as adiponectin, the concentrations of which are decreased in obesity. Interestingly, an increase in adipose
tissue expression of another anti-inflammatory IL-1 family member, namely IL-37, has been observed
after weight loss [8]. Changes in the expression pattern of IL-37 resemble those for adiponectin and
its expression after weight loss was almost 500-times higher in adipose tissue vs. liver tissue. Excessive
weight loss, as achieved after bariatric surgery, dramatically reduces expression of IL-1 family members,
(i.e. IL-6 and TNFα) in adipose and liver tissue, thereby potentially contributing to the improvement of
IR and inflammation in NAFLD patients.
Conclusion
The concept that the intestinal microbiota plays a role in NAFLD/NASH is now strongly supported
by many preclinical studies and has many attractions as it could explain very diverse aspects of these
diseases. A dysbiosis could reflect an early event in patients with NAFLD and result in activation of
many innate immune processes. Cytokines have emerged as major players in obesity and obesity-related
disorders. They direct and control low-grade inflammation which most likely contributes significantly
to disease phenotypes associated with and observed in severe obesity. Many different organs are affected
by obesity and associated metabolic inflammation, including the liver, pancreas, heart and blood vessels.
Therefore, multiple parallel hits might contribute to the evolution of inflammation in NASH, and both
the gastrointestinal tract and the adipose tissue might reflect two major players [9]. As fibrosis is driven
in most cases by inflammatory events [10], targeting inflammatory pathways and their initiating events
remains a key treatment strategy in NASH.
References
[1] Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014;147:577-594
e571.
[2] Mehal WZ.The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol
2013;10:637-644.
[3] Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance
in mice lacking TNF-alpha function. Nature 1997;389:610-614.
[4] Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001;34:1158-
1163.
[5] Wigg AJ, Roberts-Thomson IC, Dymock RB, et al.The role of small intestinal bacterial overgrowth,
intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of
non-alcoholic steatohepatitis. Gut 2001;48:206-211.
[6] Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and
improve nonalcoholic fatty liver disease. Hepatology 2003;37:343-350.
[7] Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota
in mice lacking Toll-like receptor 5. Science 2010;328:228-231.
[8] Moschen AR, Molnar C, Enrich B, et al. Adipose and liver expression of interleukin (IL)-1 family
members in morbid obesity and effects of weight loss. Mol Med 2011;17:840-845.
[9] Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple
parallel hits hypothesis. Hepatology 2010;52:1836-1846.
[10] Argo CK, Northup PG, Al-Osaimi AM, et al. Systematic review of risk factors for fibrosis
progression in non-alcoholic steatohepatitis. J Hepatol 2009;51:371-379.
86 Postgraduate Course Syllabus • Metabolic Liver Disease
adipose tissue, however, is also a major source of ‘beneficial’, i.e. anti-inflammatory, adipocytokines such
as adiponectin, the concentrations of which are decreased in obesity. Interestingly, an increase in adipose
tissue expression of another anti-inflammatory IL-1 family member, namely IL-37, has been observed
after weight loss [8]. Changes in the expression pattern of IL-37 resemble those for adiponectin and
its expression after weight loss was almost 500-times higher in adipose tissue vs. liver tissue. Excessive
weight loss, as achieved after bariatric surgery, dramatically reduces expression of IL-1 family members,
(i.e. IL-6 and TNFα) in adipose and liver tissue, thereby potentially contributing to the improvement of
IR and inflammation in NAFLD patients.
Conclusion
The concept that the intestinal microbiota plays a role in NAFLD/NASH is now strongly supported
by many preclinical studies and has many attractions as it could explain very diverse aspects of these
diseases. A dysbiosis could reflect an early event in patients with NAFLD and result in activation of
many innate immune processes. Cytokines have emerged as major players in obesity and obesity-related
disorders. They direct and control low-grade inflammation which most likely contributes significantly
to disease phenotypes associated with and observed in severe obesity. Many different organs are affected
by obesity and associated metabolic inflammation, including the liver, pancreas, heart and blood vessels.
Therefore, multiple parallel hits might contribute to the evolution of inflammation in NASH, and both
the gastrointestinal tract and the adipose tissue might reflect two major players [9]. As fibrosis is driven
in most cases by inflammatory events [10], targeting inflammatory pathways and their initiating events
remains a key treatment strategy in NASH.
References
[1] Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014;147:577-594
e571.
[2] Mehal WZ.The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol
2013;10:637-644.
[3] Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance
in mice lacking TNF-alpha function. Nature 1997;389:610-614.
[4] Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and
TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001;34:1158-
1163.
[5] Wigg AJ, Roberts-Thomson IC, Dymock RB, et al.The role of small intestinal bacterial overgrowth,
intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of
non-alcoholic steatohepatitis. Gut 2001;48:206-211.
[6] Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and
improve nonalcoholic fatty liver disease. Hepatology 2003;37:343-350.
[7] Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota
in mice lacking Toll-like receptor 5. Science 2010;328:228-231.
[8] Moschen AR, Molnar C, Enrich B, et al. Adipose and liver expression of interleukin (IL)-1 family
members in morbid obesity and effects of weight loss. Mol Med 2011;17:840-845.
[9] Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple
parallel hits hypothesis. Hepatology 2010;52:1836-1846.
[10] Argo CK, Northup PG, Al-Osaimi AM, et al. Systematic review of risk factors for fibrosis
progression in non-alcoholic steatohepatitis. J Hepatol 2009;51:371-379.
86 Postgraduate Course Syllabus • Metabolic Liver Disease
