leptin and Hepatitis--Animal

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.

Topics: Alanine Transaminase; Animals; Cell Line; Cytokines; Diet, High-Fat; Fatty Liver; Gene Expression; Hepatitis, Animal; Humans; Leptin; Lipopolysaccharide Receptors; Lipopolysaccharides; Liver Cirrhosis; Liver Cirrhosis, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Signal Transduction; STAT3 Transcription Factor; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha