Publication Date:
2012-02-03
Description:
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-alpha expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276682/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276682/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Henao-Mejia, Jorge -- Elinav, Eran -- Jin, Chengcheng -- Hao, Liming -- Mehal, Wajahat Z -- Strowig, Till -- Thaiss, Christoph A -- Kau, Andrew L -- Eisenbarth, Stephanie C -- Jurczak, Michael J -- Camporez, Joao-Paulo -- Shulman, Gerald I -- Gordon, Jeffrey I -- Hoffman, Hal M -- Flavell, Richard A -- K08A1085038/PHS HHS/ -- P30 DK-45735/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- P30 DK045735-14/DK/NIDDK NIH HHS/ -- R01 DK-40936/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01DK076674-01/DK/NIDDK NIH HHS/ -- R24 DK-085638/DK/NIDDK NIH HHS/ -- T32HL007974/HL/NHLBI NIH HHS/ -- U24 DK-059635/DK/NIDDK NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 1;482(7384):179-85. doi: 10.1038/nature10809.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22297845" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis Regulatory Proteins
;
Carrier Proteins/metabolism
;
Choline
;
Colon/microbiology
;
Cytoskeletal Proteins/deficiency
;
Disease Models, Animal
;
*Disease Progression
;
Fatty Liver/genetics/*metabolism/*pathology
;
Inflammasomes/*metabolism
;
Inflammation/metabolism/pathology
;
Interleukin-18/deficiency
;
Male
;
Metagenome
;
Methionine/deficiency
;
Mice
;
Mice, Inbred C57BL
;
Non-alcoholic Fatty Liver Disease
;
Obesity/*metabolism/*pathology
;
RNA, Ribosomal, 16S/genetics
;
Receptors, Cell Surface/metabolism
;
Toll-Like Receptor 4/deficiency/metabolism
;
Toll-Like Receptor 9/deficiency/metabolism
;
Tumor Necrosis Factor-alpha/deficiency/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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