Abstract
BackgroundRed yeast rice (RYR), a nutraceutical with a profound cholesterol-lowering effect, was found to attenuate non-alcoholic fatty liver disease (NAFLD) in mice. Despite monacolin K in RYR being a specific inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMCGR), the mechanisms underlying the protective effects of RYR against NAFLD are not fully elucidated.MethodsUsing a mouse model of high-fat diet (HFD) feeding and a cellular model of HepG2 cells challenged by lipopolysaccharide (LPS) and palmitic acid (PA), the possible molecular mechanisms were exploited in the aspects of NF-κB/NLRP3 inflammasome and mTORC1-SREBPs signaling pathways by examining the relevant gene/protein expressions. Subsequently, the correlation between these two signals was also verified using cellular experiments.ResultsRYR ameliorated lipid accumulation and hepatic inflammation in vivo and in vitro. RYR improved lipid metabolism through modulating mTORC1-SREBPs and their target genes related to triglyceride and cholesterol synthesis. Furthermore, RYR suppressed hepatic inflammation by inhibiting the NF-κB/NLRP3 inflammasome signaling. Interestingly, the treatment with RYR or MCC950, a specific NLRP3 inhibitor, resulted in the reduced lipid accumulation in HepG2 cells challenged by LPS plus PA, suggesting that the inhibitory effects of RYR on NLRP3 inflammasome-mediated hepatic inflammation may partially, in turn, contribute to the lipid-lowering effect of RYR.ConclusionsThe modulation of NF-κB/NLRP3 inflammasome and lipid synthesis may contribute to the ameliorative effects of RYR against HFD-induced NAFLD.
Highlights
Red yeast rice (RYR), a nutraceutical with a profound cholesterol-lowering effect, was found to attenu‐ ate non-alcoholic fatty liver disease (NAFLD) in mice
The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) belongs to the pattern recognition receptors (PPRs) family, which is consist of NLRP3 protein, apoptosis-associated speck-like protein containing a CARD (ASC), and cysteinyl aspartate specific proteinase-1, the complexes of which is termed as NLRP3 inflammasome [4]
The activation of NLRP3 inflammasome upon the sensation of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) causes the cleavage of caspase-1, which subsequently cleaves pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18 [5, 6]
Summary
Using a mouse model of high-fat diet (HFD) feeding and a cellular model of HepG2 cells challenged by lipopolysaccharide (LPS) and palmitic acid (PA), the possible molecular mechanisms were exploited in the aspects of NF-κB/NLRP3 inflammasome and mTORC1-SREBPs signaling pathways by examining the relevant gene/protein expressions. The correlation between these two signals was verified using cellular experiments. Animals and treatments C57BL/6J mice were purchased from Animal Research Core, University of Macau. After a week of adaption, male C57BL/6J mice (7-week-old) were fed a control diet (CON, D12450J, n = 6), a HFD (D12492, n = 10), and an HFD supplemented with RYR powder (HFD+RYR, n = 10, Hep Biotech Co., Ltd, Ningbo, China) for 16 weeks. The HFD+RYR diet, containing 5.1 g/kg RYR powder that consists of 3% of Monacolin K, provided the mice with RYR at a daily dose of 11.22 mg/kg body weight. The diet composition of each group is shown in Additional file 1: Table S1. Food intake was monitored three times a week and shown in Additional file 1: Figure S2. All animal experiments were approved by the Animal Research Ethics Committee (Approval No AEC-13-002-1), Institute of Chinese Medical Sciences, University of Macau
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