Mutation in the distal NPxY motif of LRP1 alleviates dietary cholesterol-induced dyslipidemia and tissue inflammation
| Autor: | Anja Jaeschke, David Y. Hui, Anton J.M. Roebroek, April Haller, Christopher Nam, Emily Igel, James G. Cash |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
PSD-95 post-synaptic density protein 95 LIVER Adipose tissue PROTEIN 030204 cardiovascular system & hematology Biochemistry LF low-fat Cholesterol Dietary lipoproteins/receptors IL-1β interleukin 1β 0302 clinical medicine Endocrinology insulin resistance BINDING Hyperinsulinemia TGFβ transforming growth factor beta Fatty liver NASH INSULIN TNFα tumor necrosis factor α DENSITY-LIPOPROTEIN RECEPTOR DEFICIENCY HFHC high-fat high cholesterol OBESITY metabolic studies MCP1 monocyte chemoattractant protein-1 CLS crown-like structures Life Sciences & Biomedicine Research Article GSK3β glycogen synthase kinase 3 beta EXPRESSION medicine.medical_specialty Biochemistry & Molecular Biology Foxo1 forkhead box O1 CCL C-C motif chemokine ligand LRP1 CD cluster of differentiation QD415-436 AKT protein kinase B 03 medical and health sciences Insulin resistance HF high-fat EMR1 EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 gene MIP1α macrophage inflammatory protein-1α Internal medicine NAFLD medicine LRP1 LDL receptor-related protein-1 MODULATION Liver X receptor ARC activity regulated cytoskeleton associated protein Science & Technology business.industry PCSK9 Cell Biology medicine.disease MICE 030104 developmental biology ABCA1 ATP binding cassette subfamily A member 1 inflammation LDL receptor cholesterol metabolism LXR liver X receptor Steatohepatitis business PCSK9 proprotein convertase subtilisin/kexin type 9 |
| Zdroj: | Journal of Lipid Research, Vol 62, Iss, Pp 100012-(2021) Journal of Lipid Research |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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