Acute Psychological Stress Accelerates Reverse Cholesterol Transport via Corticosterone-Dependent Inhibition of Intestinal Cholesterol Absorption

Abstract

Rationale: Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress-inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well-understood. Objective: To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion. Methods and Results: C57Bl/6J mice were exposed to restraint stress for 3 hours to induce acute psychological stress. RCT in vivo was quantified by measuring the transfer of [ 3 H]cholesterol from intraperitoneally injected mouse macrophages to the lumen of the small intestine within the stress period. Surprisingly, stress markedly increased the contents of macrophage-derived [ 3 H]cholesterol in the intestinal lumen. In the stressed mice, intestinal absorption of [ 14 C]cholesterol was significantly impaired, the intestinal mRNA expression level of peroxisome proliferator–activated receptor-α increased, and that of the sterol influx transporter Niemann-Pick C1–like 1 decreased. The stress-dependent effects on RCT rate and peroxisome proliferator–activated receptor-α gene expression were fully mimicked by administration of the stress hormone corticosterone (CORT) to nonstressed mice, and they were blocked by the inhibition of CORT synthesis in stressed mice. Moreover, the intestinal expression of Niemann-Pick C1–like 1 protein decreased when circulating levels of CORT increased. Of note, when either peroxisome proliferator-activated receptor α or liver X receptor α knockout mice were exposed to stress, the RCT rate remained unchanged, although plasma CORT increased. This indicates that activities of both transcription factors were required for the RCT-accelerating effect of stress. Conclusions: Acute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating CORT.

Effect of Conjugated Bile Salt Taurodeoxycholic Acid (TDCA) on Mice Colonic Motor Activity

“…Psychological stress plays a major role in functional gastrointestinal disorders, it induced activation or sensitization of mucosal mast cells in the GI tract seem to be involved in stress-associated alterations of visceral sensitivity (20). Psychological stress accelerated reverse cholesterol transport (RCT) by compromising intestinal cholesterol absorption (21) confirming the increase in releasing of TDCA to inhibit the intestinal motility.…”

High-Density Lipoprotein

“…55,56 Novel bottlenecks of RCT (eg, intestinal cholesterol resorption by NPC1L1) were identified using this model. 57 It also contributed to the growing evidence for the existence of a liver-and HDL-independent RCT pathway, the so-called transintestinal cholesterol excretion. 58 Notably, compared with HDL-C levels, the activity of macrophage-specific RCT also showed stronger correlations with atherosclerosis in different animal models with disturbed HDL metabolism.…”

Restraint Stress Restrains Cholesterol in the Intestine

“…Some bile acids are also resecreted on the apical site by MRP2 (ABCC2). 18 For their experiments, Silvennoinen et al 9 used an RCT model, which was originally described by Rader, Rothblat, and colleagues 19 : Peritoneal or bone-marrow-derived macrophages are labeled with radioactive cholesterol and then installed into the peritoneum of recipient mice for the measurement of radioactive cholesterol taken up into plasma or liver, as well as excretion into feces. 19 In this model of macrophage-specific RCT, 19 unlike in whole-body RCT models, 20 interferences with either the cellular cholesterol efflux machinery (eg, by Figure. Reverse transport of macrophage-derived cholesterol in nonstressed (A) and stressed mice (B).…”

“…In this issue of Circulation Research, Silvennoinen et al 9 investigated the effects of stress and corticosterone, the stress hormone of rodents, on cholesterol homeostasis in mice. They focused on reverse cholesterol transport (RCT) that describes the transport of excess cholesterol from peripheral cells to the liver for excretion into the bile, either directly or indirectly after conversion into bile acids, or to steroidogenic organs for hormone production (Figure).…”

“…The indirect pathway is mediated by the cholesteryl ester transfer protein that exchanges cholesteryl esters of HDL with triglycerides of apoB-containing lipoproteins. 10,12 Mice, however, do not express cholesteryl ester transfer protein, so this pathway is not operative in the model used by Silvennoinen et al 9 Two direct pathways are mediated by HDL receptors, one well-characterized involving the selective uptake of lipids into the liver and steroidogenic organs via scavenger receptor-BI (SR-BI) that is also crucial for the supply of steroidogenic organs, including adrenals, with cholesterol. 13 The other less characterized holoparticle uptake is stimulated by the interaction of apoA-I with ectopic F0F1-ATPase and subsequent activation of the P2Y13 receptor.…”