The capsaicinoid nonivamide suppresses the inflammatory response and attenuates the progression of steatosis in a NAFLD-rat model.

Nonalcoholic fatty liver disease (NAFLD) is relatively associated with comorbidities in obesity and metabolic inflammation. Low-grade inflammation following the high-fat diet (HFD)-induced NAFLD can promote the development of nonalcoholic steatohepatitis (NASH) through particularly liver-resident immune cell recruitment and hepatic nuclear factor kappa B (NF-κB) pathway. Therefore, inflammatory intervention may contribute to NASH reduction. Pelargonic acid vanillylamide (PAVA) or nonivamide is one of the pungent capsaicinoids of Capsicum species and has been found in chili peppers. Our previous study demonstrated that PAVA improved hepatic function, decreased oxidative stress and reduced apoptotic cell death but the insight role of PAVA on NAFLD is still unclear. Thus, this study aimed to investigate the underlying anti-inflammatory mechanism of PAVA in an NAFLD-rat model. Male Sprague Dawley rats were fed with normal diet or HFD for 16 weeks. Then high-fat rats were given vehicle or PAVA (1 mg/kg/day) for another 4 weeks. We found that PAVA alleviated hepatic inflammation associated with the reducing toll-like receptor 4/NF-κB pathway, showing significantly lower recruitment of cluster of differentiation 44. PAVA also maintained activity of insulin signaling pathway, and attenuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome formation. NAFLD progresses to NASH through transforming growth factor (TGF-β1), and also recovery to simple stage followed by PAVA suppresses pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Therefore, our findings suggest that PAVA provides a novel therapeutic approach for NAFLD and slows the progression to NASH.