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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Program Projects (P01)
Project #
2P01AT003961-06A1
Application #
8739827
Study Section
Special Emphasis Panel (ZAT1)
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Type
DUNS #
City
Columbia
State
SC
Country
United States
Zip Code
29208
Miranda, Kathryn; Yang, Xiaoming; Bam, Marpe et al. (2018) MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages. Int J Obes (Lond) 42:1140-1150
Alhasson, Firas; Seth, Ratanesh Kumar; Sarkar, Sutapa et al. (2018) High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol 17:1-15
Hofseth, Lorne J (2018) Getting rigorous with scientific rigor. Carcinogenesis 39:21-25
Abron, Jessicca D; Singh, Narendra P; Murphy, Angela E et al. (2018) Differential role of CXCR3 in inflammation and colorectal cancer. Oncotarget 9:17928-17936
Bam, Marpe; Yang, Xiaoming; Sen, Souvik et al. (2018) Characterization of Dysregulated miRNA in Peripheral Blood Mononuclear Cells from Ischemic Stroke Patients. Mol Neurobiol 55:1419-1429
Elliott, David M; Singh, Narendra; Nagarkatti, Mitzi et al. (2018) Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells. Front Immunol 9:1782
Kenne, Gabriel J; Gummadidala, Phani M; Omebeyinje, Mayomi H et al. (2018) Activation of Aflatoxin Biosynthesis Alleviates Total ROS in Aspergillus parasiticus. Toxins (Basel) 10:
Bader, Jackie E; Enos, Reilly T; Velázquez, Kandy T et al. (2018) Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer. Am J Physiol Gastrointest Liver Physiol 314:G22-G31
Wirth, Michael D; Sevoyan, Maria; Hofseth, Lorne et al. (2018) The Dietary Inflammatory Index is associated with elevated white blood cell counts in the National Health and Nutrition Examination Survey. Brain Behav Immun 69:296-303
Becker, William; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2018) miR-466a Targeting of TGF-?2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation. Front Immunol 9:688

Showing the most recent 10 out of 178 publications