Therapeutic Effect Of KS-356, A Novel Small Compound Targeting CD147, on Mice with NAFLD through Modulating the Inflammatory Crosstalk between Liver and Visceral Adipose Tissue: An 18F-FDG PET/CT Study

Abstract

Aims: Inflamed and dysregulated visceral adipose tissue (VAT) secretes pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) thereby promoting systemic inflammation and insulin resistance which further lead to exacerbate the progression of nonalcoholic fatty liver disease (NAFLD). CD147 has been known to play key roles in mediating the inflammatory activation of macrophages through the activation of matrix metalloproteinase-9 (MMP-9). We identified that a novel drug KS-356 could bind to CD147 and inhibit its subsequent MMP-9 activation. Here, we investigated the suppressive effects of a novel drug KS-356 on NAFLD and inflamed VAT using high-fat induced mouse model and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT), which is a well-known non-invasive imaging modality for measurement of inflammatory activity, especially M1 macrophage.

Methods: NAFLD was induced by a high-fat diet (HFD) (60% fat) for 20 weeks using the C57BL/6 mice. KS-356 (50 mg/kg) was orally given daily for 20 weeks. Both insulin tolerance- and glucose-tolerance were performed to assess the status of insulin-resistance and glucose-intolerance. Before sacrifice, blood serum was acquired to analysis of C-reactive protein (CRP) levels and 18F-FDG PET/CT was taken. After sacrifice, histomolecular analysis was performed on harvested liver and VAT.

Results: KS-356 significantly improved insulin sensitivity with glucose homeostasis and reduced the progression of NAFLD. Furthermore, KS-356 also ameliorated VAT inflammation and its related systemic inflammation. There was no significant difference of daily food intake between HFD and HFD with KS-356 group.

Conclusions: Owing to its beneficial effect across the liver-VAT-metabolic continuum, KS-356 could be a potential therapeutic drug candidate for NAFLD and related metabolic disorder.