title: Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9.
abstract: Nonalcoholic steatohepatitis (NASH) is the most common liver disease in industrialized countries. NASH is a progressive disease that can lead to cirrhosis, cancer, and death, and there are currently no approved therapies. The development of NASH in animal models requires intact TLR9, but how the TLR9 pathway is activated in NASH is not clear. Our objectives in this study were to identify NASH-associated ligands for TLR9, establish the cellular requirement for TLR9, and evaluate the role of obesity-induced changes in TLR9 pathway activation. We demonstrated that plasma from mice and patients with NASH contains high levels of mitochondrial DNA (mtDNA) and intact mitochondria and has the ability to activate TLR9. Most of the plasma mtDNA was contained in microparticles (MPs) of hepatocyte origin, and removal of these MPs from plasma resulted in a substantial decrease in TLR9 activation capacity. In mice, NASH development in response to a high-fat diet required TLR9 on lysozyme-expressing cells, and a clinically applicable TLR9 antagonist blocked the development of NASH when given prophylactically and therapeutically. These data demonstrate that activation of the TLR9 pathway provides a link between the key metabolic and inflammatory phenotypes in NASH.
authors.forename: Irma
authors.initials: I
authors.lastname: Garcia-Martinez
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Chen
authors.forename: Rafaz
authors.initials: R
authors.lastname: Hoque
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.forename: Sonia
authors.initials: S
authors.lastname: Caprio
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.forename: Robert Lee
authors.initials: RL
authors.lastname: Coffman
authors.forename: Albert
authors.initials: A
authors.lastname: Candia
authors.forename: Wajahat Zafar
authors.initials: WZ
authors.lastname: Mehal
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D004272:DNA, Mitochondrial / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000276:immunology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha