Author
Listed:
- Jorge Henao-Mejia
(Yale University School of Medicine)
- Eran Elinav
(Yale University School of Medicine)
- Chengcheng Jin
(Yale University School of Medicine
Yale University School of Medicine)
- Liming Hao
(Yale University School of Medicine)
- Wajahat Z. Mehal
(Yale University School of Medicine)
- Till Strowig
(Yale University School of Medicine)
- Christoph A. Thaiss
(Yale University School of Medicine)
- Andrew L. Kau
(Center for Genome Sciences and Systems Biology, Washington University School of Medicine
Washington University School of Medicine)
- Stephanie C. Eisenbarth
(Yale University School of Medicine)
- Michael J. Jurczak
(Yale University School of Medicine)
- Joao-Paulo Camporez
(Yale University School of Medicine)
- Gerald I. Shulman
(Yale University School of Medicine
Howard Hughes Medical Institute)
- Jeffrey I. Gordon
(Center for Genome Sciences and Systems Biology, Washington University School of Medicine)
- Hal M. Hoffman
(Rady Children’s Hospital San Diego, University of California at San Diego)
- Richard A. Flavell
(Yale University School of Medicine
Howard Hughes Medical Institute)
Abstract
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)-α 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.
Suggested Citation
Jorge Henao-Mejia & Eran Elinav & Chengcheng Jin & Liming Hao & Wajahat Z. Mehal & Till Strowig & Christoph A. Thaiss & Andrew L. Kau & Stephanie C. Eisenbarth & Michael J. Jurczak & Joao-Paulo Campor, 2012.
"Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity,"
Nature, Nature, vol. 482(7384), pages 179-185, February.
Handle:
RePEc:nat:nature:v:482:y:2012:i:7384:d:10.1038_nature10809
DOI: 10.1038/nature10809
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Cited by:
- Jukka Hintikka & Sanna Lensu & Elina Mäkinen & Sira Karvinen & Marjaana Honkanen & Jere Lindén & Tim Garrels & Satu Pekkala & Leo Lahti, 2021.
"Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering,"
IJERPH, MDPI, vol. 18(8), pages 1-24, April.
- Kaiser Wani & Hind AlHarthi & Amani Alghamdi & Shaun Sabico & Nasser M. Al-Daghri, 2021.
"Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders,"
IJERPH, MDPI, vol. 18(2), pages 1-21, January.
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