Endothelial LRP1 regulates metabolic responses by acting as a co-activator of PPARγ

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) regulates lipid and glucose metabolism in liver and adipose tissue. It is also involved in central nervous system regulation of food intake and leptin signalling. Here we demonstrate that endothelial Lrp1 regulates systemic energy homeostasis. Mice with endothelial-specific Lrp1 deletion display improved glucose sensitivity and lipid profiles combined with increased oxygen consumption during high-fat-diet-induced obesity. We show that the intracellular domain of Lrp1 interacts with the nuclear receptor Pparγ, a central regulator of lipid and glucose metabolism, acting as its transcriptional co-activator in endothelial cells. Therefore, Lrp1 not only acts as an endocytic receptor but also directly participates in gene transcription. Our findings indicate an underappreciated functional role of endothelium in maintaining systemic energy homeostasis.

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…So the basal levels of LRP1 act as an essential gatekeeper for β cells during DIO. Two recent studies demonstrated LRP1 as a PPARγ coactivator in endothelial cells (45) and in macrophages (46). In contrast, in the context of the β cell, we show here that LRP1 suppresses PPARγ2.…”

“…Tail blood glucose was measured at 0, 3, 6, and 10 minutes and then every 5 minutes until 120 minutes. Blood samples to measure plasma insulin were taken at 0, 3,6,10,15,20,30,45,60,90, and 120 minutes.…”

LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation

“…Additionally, LRP1β can be further processed 36 and translocated to nucleus, where it interacts with nuclear proteins such as poly(ADP-ribose) polymerase-1 (PARP-1) 24 and PPARγ 25 to regulate cell cycle progression and gene transcription. Interestingly, we observed that LRP1β and its processed intracellular domain (~12 kDa) were localized in the nucleus at basal condition and their levels were decreased following the treatment of DAPT, a γ-secretase inhibitor (an inhibitor of presenillin-dependent γ-secretase activity, to generate the intracellular domain of LRP1 (~12 kDa) from the ~25 kDa processed form 24, 36 ; VA-B).…”

“…LRP1 is an endocytic receptor for multiple signaling pathways and mediates their signals through its β chain, which interacts with many scaffolding proteins 17–23 . In addition, processed forms of LRP1β can also translocate into nucleus and regulate the enzyme activity of PARP1 24 and expression of PPAR target genes by acting as a PPARγ co-activator 25 . Although LRP1 is required for the endocytosis of BMPER signaling complex in endothelial cells, it remains elusive whether the coupling of BMPER to LRP1 may also initiate their own signaling events.…”

LRP1 Regulates Peroxisome Biogenesis and Cholesterol Homeostasis in Oligodendrocytes and is Required in CNS Myelin Development and Repair

“…Lrp1 control and Lrp1 --/--OLs, we observed a 788 significant drop in peroxisomes along radial processes of MBP + OLs (Figure 5e--5h). 789 790 PPARγ, a key regulator of lipid and glucose metabolism (Mao et al, 2017). Activated PPARγ 851 moves into the nucleus to control gene expression by binding to PPAR--responsive elements 852 (PPREs) on numerous target genes, including Lrp1 (Gauthier et al, 2003).…”