title: Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling.
abstract: Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.
authors: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Yokohama, Japan.
authors: Kento
authors: K
authors: Imajo
authors: Koji
authors: K
authors: Fujita
authors: Masato
authors: M
authors: Yoneda
authors: Yuichi
authors: Y
authors: Nozaki
authors: Yuji
authors: Y
authors: Ogawa
authors: Yoshiyasu
authors: Y
authors: Shinohara
authors: Shingo
authors: S
authors: Kato
authors: Hironori
authors: H
authors: Mawatari
authors: Wataru
authors: W
authors: Shibata
authors: Hiroshi
authors: H
authors: Kitani
authors: Kenichi
authors: K
authors: Ikejima
authors: Hiroyuki
authors: H
authors: Kirikoshi
authors: Noriko
authors: N
authors: Nakajima
authors: Satoru
authors: S
authors: Saito
authors: Shiro
authors: S
authors: Maeyama
authors: Sumio
authors: S
authors: Watanabe
authors: Koichiro
authors: K
authors: Wada
authors: Atsushi
authors: A
authors: Nakajima
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015870:Gene Expression; D006520:Hepatitis, Animal / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020738:Leptin / Q000378:metabolism* / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008103:Liver Cirrhosis; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D020738:Leptin; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase