Ayaori, M. | Search bioRxiv

bioRxiv2023

Liver-specific LXR inhibition represses reverse cholesterol transport in cholesterol-fed mice

ObjectiveHigh density lipoprotein (HDL) exerts an anti-atherosclerotic effect via reverse cholesterol transport (RCT). Several phases of RCT are transcriptionally controlled by Liver X receptors (LXRs). Although macrophage LXRs reportedly promote RCT, it is still uncertain whether hepatic LXRs affect RCT in vivo. Approach and ResultsTo address this question, we induced hepatic overexpression of sulfotransferase family cytosolic 2B member 1 (Sult2b1) in mice. Sult2b1 facilitates generation of sulfated cholesterol, resulting in reduced production of LXR ligands (oxysterols), which impairs LXR signaling. Adenoviral vectors expressing Sult2b1 (Ad-Sult2b1) or luciferase were intravenously injected into mice under a normal or high-cholesterol diet. Hepatic Sult2b1 overexpression resulted in reduced expression of LXR-target genes - ATP-binding cassette transporter G5/G8, cholesterol 7 hydroxylase and LXR itself - respectively reducing or increasing cholesterol levels in HDL and apolipoprotein B-containing lipoproteins (apoB-L). A macrophage RCT assay revealed that Sult2b1 overexpression inhibited fecal excretion of macrophage-derived 3H-cholesterol only under a high-cholesterol diet. In a HDL kinetic study, Ad-Sult2b1 promoted catabolism/hepatic uptake of HDL-derived cholesterol, thereby reducing fecal excretion. We next performed an in vitro lipoprotein production assay which revealed a Sult2b1-mediated reduction/increase in HDL or apoB-L secretion from hepatocytes, respectively. Finally, in LXR/{beta} double knockout mice, hepatic Sult2b1 overexpression increased apoB-L levels, but there were no differences in HDL levels or RCT compared to the control, indicating that Sult2b1-mediated effects on HDL/RCT and apoB-L were distinct: the former was LXR-dependent, but not the latter. ConclusionsHepatic LXR inhibition negatively regulates circulating HDL levels and RCT by reducing LXR-target gene expression. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/527401v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@18ff927org.highwire.dtl.DTLVardef@12e776corg.highwire.dtl.DTLVardef@1a26ebaorg.highwire.dtl.DTLVardef@113b5c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2020

Mechanical impact on the head has an antihypertensive effect

Physical exercise is known to be beneficial for various brain functions. However, the mechanisms behind the positive effects of exercise on the brain remain to be elucidated. Here we show that passive head motion in hypertensive rats, which reproduces the mechanical accelerations generated in their heads during moderate-velocity treadmill running, decreases the expression of angiotensin II type 1 receptor (AT1R) in astrocytes in the rostral ventrolateral medulla (RVLM), thereby lowering blood pressure. Passive head motion generates interstitial fluid movement that is estimated to exert shear stress with an average magnitude of <1 Pa on the cells in the rat medulla. Fluid shear stress of a sub-Pa magnitude decreases AT1R expression in cultured astrocytes. In hypertensive rats, inhibition of interstitial fluid movement following hydrogel introduction to the RVLM eliminates the antihypertensive effects of passive head motion and treadmill running. Furthermore, vertically oscillating chair riding by hypertensive adult humans, which reproduces the mechanical accelerations generated in their heads during light jogging or fast walking, lowers their blood pressure. Our findings indicate that moderate mechanical intervention can have antihypertensive effects by modulating the function of RVLM astrocytes through interstitial fluid shear stress. We anticipate that mechanical regulation is responsible for a variety of the positive effects of physical exercise on human health, particularly those related to brain functions.

bioengineering↗