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蛋白酶激活受体 2（PAR2）下调脂肪组织脂蛋白脂肪酶（LPL）导致甘油三酯血症的发生。

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

机构信息

College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.

College of Life and Environment Sciences, Wenzhou University, Wenzhou, Zhejiang, China.

出版信息

JCI Insight. 2024 Jul 8;9(13):e173240. doi: 10.1172/jci.insight.173240.

DOI:10.1172/jci.insight.173240
PMID:38973609
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11383372/
Abstract

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

摘要

脂蛋白脂肪酶 (LPL) 水解循环中的甘油三酯 (TGs)，释放脂肪酸 (FA)，并促进白色脂肪组织 (WAT) 中的脂质储存。然而，调节脂肪 LPL 的机制及其与高甘油三酯血症发展的关系在很大程度上尚不清楚。肥胖人群的 WAT 表现出高 PAR2 表达，PAR2 与 LPL 基因呈负相关。LPL 表达的降低也与血浆 TG 水平的升高呈负相关，表明脂肪 PAR2 可能通过下调 LPL 来调节高甘油三酯血症。在小鼠中，衰老和高棕榈酸饮食 (PD) 增加了 WAT 中的 PAR2 表达，这与高水平的巨噬细胞迁移抑制因子 (MIF) 有关。MIF 通过与 CXCR2/4 受体结合并抑制 Akt 磷酸化，下调脂肪细胞中的 LPL 表达和活性。在 MIF 过表达模型中，高循环 MIF 水平抑制脂肪 LPL，这种抑制与血浆 TG 增加而不是 FA 增加有关。在 PD 喂养后，脂肪 LPL 的表达和活性显著降低，而在 Par2-/- 小鼠中则得到逆转。重组 MIF 输注恢复了 Par2-/- 小鼠中的高血浆 MIF 水平，降低了 LPL 并减弱了脂肪细胞的脂质储存，导致高甘油三酯血症。这些数据表明，PAR2/MIF 下调脂肪 LPL 可能导致高甘油三酯血症的发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/0ebb3a7e94e6/jciinsight-9-173240-g046.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/44d18d8b7db5/jciinsight-9-173240-g041.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/2c1974b785bd/jciinsight-9-173240-g042.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/92a46f4ecad8/jciinsight-9-173240-g043.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/1b590f5c8a14/jciinsight-9-173240-g044.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/aa7676e18ee8/jciinsight-9-173240-g045.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/0ebb3a7e94e6/jciinsight-9-173240-g046.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/44d18d8b7db5/jciinsight-9-173240-g041.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/2c1974b785bd/jciinsight-9-173240-g042.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/92a46f4ecad8/jciinsight-9-173240-g043.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/1b590f5c8a14/jciinsight-9-173240-g044.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/aa7676e18ee8/jciinsight-9-173240-g045.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbc0/11383372/0ebb3a7e94e6/jciinsight-9-173240-g046.jpg

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