Protease-activated receptor 2 (PAR2) regulates inflammatory responses and lipid metabolism. However, its precise role in colitis remains unclear. Here, we aimed to investigate the function of PAR2 in high-fat diet fed mice with colitis and its potential role in autophagy. PAR2^+/+ and PAR2^-/- mice were fed a high-fat diet (HFD) for 7 days before colitis induction with dextran sodium sulfate. Deletion of PAR2 and a HFD significantly exacerbated colitis as shown by increased mortality, body weight loss, diarrhea or bloody stools, colon length shortening, and mucosal damage. Pro-inflammatory cytokine levels were elevated in HFD-fed PAR2^-/- mice and in cells treated with the PAR2 antagonist GB83, palmitic acid (PA), and a cytokine cocktail (CC). Damaging effects of PAR2 blockage were associated with autophagy regulation by reducing the levels of YAP1, SIRT1, PGC-1α, Atg5, and LC3A/B-I/II. Additionally, mitochondrial dysfunction was demonstrated only in cells treated with GB83, PA, and CC. Reduced cell viability and greater induction of apoptosis, as shown by increased levels of cleaved caspase-9, cleaved caspase-3, and cleaved PARP, were observed in cells treated with GB83, PA, and CC but not in those treated with only PA and CC. Collectively, protective effects of PAR2 were elucidated during inflammation accompanied by high-fat environment by promoting autophagy and inhibiting apoptosis, suggesting PAR2 as a therapeutic target for inflammatory bowel disease co-occurring with metabolic syndrome.

中文翻译：

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蛋白酶激活受体2的阻滞部分通过自噬抑制加剧了高脂环境中的炎症

蛋白酶激活受体2（PAR2）调节炎症反应和脂质代谢。但是，其在结肠炎中的确切作用仍不清楚。在这里，我们旨在研究PAR2在高脂饮食喂养的结肠炎小鼠中的功能及其在自噬中的潜在作用。在用右旋糖酐硫酸钠诱发结肠炎之前，对PAR2 ^{+ / +}和PAR2 ^-/-小鼠进行高脂饮食（HFD）喂养7天。PAR2和HFD的缺失会导致死亡率增加，体重减轻，腹泻或大便稀血，结肠长度缩短和粘膜损伤，从而加剧结肠炎。喂HFD的PAR2中促炎性细胞因子水平升高^-/-小鼠，以及用PAR2拮抗剂GB83，棕榈酸（PA）和细胞因子混合物（CC）处理的细胞中。通过降低YAP1，SIRT1，PGC-1α，Atg5和LC3A / BI / II的水平，PAR2阻滞的破坏作用与自噬调节相关。此外，仅在用GB83，PA和CC处理的细胞中证明了线粒体功能障碍。在用GB83，PA和CC处理的细胞中观察到caspase-9，caspase-3切割和PARP裂解的水平升高，从而降低了细胞活力并诱导了更大的凋亡，但在仅用PA和CC。通过促进自噬和抑制细胞凋亡，在高脂环境伴随的炎症过程中共同阐明了PAR2的保护作用，