Non-alcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease and one of leading causes of death worldwide. It is a key component of metabolic syndrome which results from obesity. The transition from simple steatosis to NASH is a crucial step in the evolution from the benign to malignant end of the spectrum. A "two-hit" model suggests that after a first hit by hepatic steatosis and insulin resistance, a second hit is needed to develop NASH. The second hit is mostly derived from gut and adipose tissue, including lipopolysaccharide (LPS), proinflammatory adipokines and toxic lipids, leading to liver inflammation. Blocking inflammation of liver due to the second hit is critical to preventing the transition from simple steatosis to NASH and further to cirrhosis and HCC. Toll-like receptors (TLRs), especially TLR2 and TLR4, have a key role in the simple steatosis-to-NASH transition. Lipid accumulation in liver causes liver cell injury and up-regulates TLR expression, especially TLR4 and TLR2 in multiple cell types, further sensitizing these cells to ligands such as gut-derived LPS. This triggers the inflammatory cascade in the liver. Therefore, with no effective therapies approved for clinical use, blocking TLR2 and TLR4 signaling in the liver is considered as a promising strategy to halt the simple steatosis-to-NASH transition. Recently we isolated and characterized a novel single compound, Sparstolonin B (SsnB), from a Chinese herb, Sparganium stoloniferum, and made an exciting discovery that SsnB is a selective TLR2 and TLR4 antagonist, which acts via disruption of TIRAP-MyD88 interaction. Our recent preliminary studies further showed that SsnB diminished NASH indicators in two mouse models, and modulated the expression of several microRNAs in the liver, which have demonstrated roles in NASH. Our central hypothesis is that SsnB can halt the transition from simple hepatic steatosis to NASH by virtue of its inhibition of TLR2 and TLR4 signaling in multiple liver cell types involving epigenetic pathways. To test this central hypothesis, we propose three aims. SA1. To examine the effects of SsnB on simple hepatic steatosis-to-NASH transition in several mouse models. In these models, LPS, CYP2E1 substrate or dietary interactions serve as the second hit for NASH development. SA2. To test the hypothesis that SsnB attenuates NASH by blocking TLR2 and TLR4 signaling in multiple cell types, including liver parenchymal cells, mesenchymal and hematopoietic cells. We will also establish in vivo the role of endotoxin from the leaky gut as the principle cause of inflammation and progression in NASH and examine the effects of SsnB on leaky gut. SA3. To elucidate the mechanisms by which SsnB modulates the expression of miR155, miR34a, miR21 and miR122 and the correlated downstream events that contribute to the pathogenesis of NASH. The studies designed above are highly significant in understanding the mode of action of SsnB in suppressing inflammation, paving ways for developing SsnB or its analogs into novel therapies for NAFLD/NASH and other related inflammatory diseases.

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