The LDL receptor-related protein-1 (LRP1) is highly expressed in numerous cell types, and its impairment is associated with obesity, diabetes, and fatty liver disease. However, the mechanisms linking LRP1 to metabolic disease are not completely understood. Here, we compared the metabolic phenotype of C57BL/6J wild type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low fat (LF) diet or high fat diets with (HFHC) or without (HF) cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, and hyperlipidemia, as well as increased adiposity with adipose tissue inflammation and liver steatosis. However, when animals were fed the HF diet supplemented with cholesterol, the LRP1 NPxY mutation prevents hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, insulin signaling is impaired in LRP1 NPxY mutant hepatocytes and this mutation does not protect against HFHC-induced insulin resistance. The selective metabolic improvement observed in HFHC-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lowering of plasma and hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice in response to HF or HFHC diet feeding indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.

中文翻译：

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LRP1 远端 NPxY 基序的突变可减轻饮食胆固醇引起的血脂异常和组织炎症。


LDL 受体相关蛋白 1 (LRP1) 在多种细胞类型中高表达，其损伤与肥胖、糖尿病和脂肪肝疾病相关。然而，LRP1 与代谢疾病的联系机制尚不完全清楚。在这里，我们比较了 C57BL/6J 野生型和在远端 NPxY 基序中携带失活突变的 LRP1 敲入小鼠在喂食低脂 (LF) 饮食或含 (HFHC) 或不含 (HF) 的高脂饮食后的代谢表型补充胆固醇。高频喂养后，两组患者均出现高血糖、高胰岛素血症和高脂血症，并且肥胖程度增加，伴有脂肪组织炎症和肝脏脂肪变性。然而，当动物喂食补充有胆固醇的 HF 饮食时，LRP1 NPxY 突变可以防止高胆固醇血症，减少脂肪组织和脑部炎症，并限制肝脏进展为脂肪性肝炎。然而，LRP1 NPxY 突变肝细胞中的胰岛素信号传导受损，并且这种突变不能防止 HFHC 诱导的胰岛素抵抗。在 HFHC 喂养的 LRP1 NPxY 突变小鼠中观察到的选择性代谢改善是由于肝脏 LDL 受体水平明显增加，导致血浆脂蛋白清除率升高以及血浆和肝脏胆固醇水平降低。 LRP1 NPxY 突变小鼠响应 HF 或 HFHC 饮食喂养而表现出的独特代谢表型表明 LRP1-胆固醇轴在调节组织炎症中。 LRP1 NPxY 突变小鼠表型与在组织特异性 LRP1 失活的小鼠中观察到的表型不同，因此凸显了采用综合方法来评估整体 LRP1 功能障碍如何促进代谢疾病发展的重要性。