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Figure 1. Lipid metabolism and NASH progression. A. The free fatty acids are released via lipolysis from adipocyte and fat tissue, B. lipid uptake from circulation, (C. and D.) de novo lipogenesis from sugars to triacylglycerol. These three pathways are the primary source of hepatic lipids. E. Lipids are cleared by β-oxidation via mitochondria and exported by very low-density lipoprotein (VLDL). Pathogenesis of NAFL is owing to the accumulation of fatty acids (>5%), which results in lipotoxicity in the hepatocytes (steatosis). NASH is a more progressive form of liver steatosis. F. Progressive liver injury caused by lipotoxicity leads to hepatocyte ballooning and activation of inflammatory responses (hepatitis). G. The inflammatory response stimulates the activation of hepatic stellate cells (HSCs) and generates extensive extracellular matrix (ECM) remodeling, leading to more severe liver fibrosis. The figure is modified from Esler WP and Bence, KK, 2019.6

Figure 2. Inhibition of Liver Fibrosis, Collagen Type I (Human ) By Reference Compound SB-431542, using Liver fibrosis collagen type I Human Functional Antagonist Assay. LX-2 cells (10000 cells/well) are plated in culture medium and incubated at 37°C, 5% CO₂ incubator for 6 hours, followed by starvation at 37°C, 5% CO₂ incubator overnight. Starved LX-2 cells are pre-incubated with test compound and/or vehicle for 20 minutes at 37°C; liver fibrosis is induced by 0.3 nM TGF-β1 after pre-incubation. After a 48-hour incubation period, cells are fixed and stained with collagen type 1. Cell images are acquired by ImageXpress Micro Confocal high-content imaging system, and the total intensity of collagen type 1 is quantified and analyzed by MetaXpress software. Inhibition by 50 percent or more (≥50%) relative to 0.3 nM TGF-β1 indicates possible inhibition of liver fibrosis.

Figure 3. Demonstrative data of the TGFβ-induced liver fibrosis cell model (A.) and the CDAHFD-induced HLCM model (B.). A. TGFβ successfully induced human hepatic stellate cell line LX-2 activation. Reported TGFβ inhibitors significantly suppressed COL1A1 expression in a dose-dependent manner. B. Liver steatosis, hepatocellular ballooning, and fibrosis were successfully induced after CDAHFD feeding in HLCM while applied clinical candidate obeticholic acid (OCA) significantly reduced total NAS + fibrosis score at 6 and 12 weeks.