Kento Imajo,
Koji Fujita,
Masato Yoneda,
Yuichi Nozaki,
Yuji Ogawa,
Yoshiyasu Shinohara,
Shingo Kato,
Hironori Mawatari,
Wataru Shibata,
Hiroshi Kitani,
Kenichi Ikejima,
Hiroyuki Kirikoshi,
Noriko Nakajima,
Satoru Saito,
Shiro Maeyama, Sumio Watanabe,
Koichiro Wada,
Atsushi Nakajima
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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.
Cell metabolism 07/2012; 16(1):44-54. · 17.35 Impact Factor
