Molecular Pathways Underlying Cholesterol Homeostasis

Abstract

Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.

Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

“…Secondly, any increase in intracellular cholesterol accumulation is known to downregulate miR-33a expression which, in turn, will alleviate miR-33a-mediated ABCA1 inhibition, leading to an increase in ABCA1 protein expression and ABCA1 efflux independently of TLR stimulation [23,48]. Taken together, these results indicate that in our experimental context, changes in miR-33a and ABCA1 expression have to be considered as the effectors of a negative feedback loop aimed at limiting anti-ApoA-1 IgG-induced intracellular lipid accumulation without being able to fully prevent it, as a common feature of negative feedback loops [49]. Nevertheless, our results indicate that in presence of anti-ApoA-1 IgG, the usual negative feedback mechanism activated by high intracellular cholesterol levels to reduce LDLR seems to be blunted [49].…”

“…Taken together, these results indicate that in our experimental context, changes in miR-33a and ABCA1 expression have to be considered as the effectors of a negative feedback loop aimed at limiting anti-ApoA-1 IgG-induced intracellular lipid accumulation without being able to fully prevent it, as a common feature of negative feedback loops [49]. Nevertheless, our results indicate that in presence of anti-ApoA-1 IgG, the usual negative feedback mechanism activated by high intracellular cholesterol levels to reduce LDLR seems to be blunted [49]. The exact mechanisms underlying this observation are currently unknown and warrant further investigations.…”

Comprehensive amelioration of high-fat diet-induced metabolic dysfunctions through activation of the PGC-1α pathway by probiotics treatment in mice

“…To maintain cholesterol homeostasis, the intricate network of cholesterol-related processes such as cholesterol biosynthesis, intestinal absorption, lipoprotein release into the blood, and transport to the liver, must be tightly regulated [37]. RCT is the major route for removal of excess cholesterol from peripheral tissues and its transport to the liver, by which HDL protects against atherosclerotic cardiovascular disease [37].…”

“…To maintain cholesterol homeostasis, the intricate network of cholesterol-related processes such as cholesterol biosynthesis, intestinal absorption, lipoprotein release into the blood, and transport to the liver, must be tightly regulated [37]. RCT is the major route for removal of excess cholesterol from peripheral tissues and its transport to the liver, by which HDL protects against atherosclerotic cardiovascular disease [37]. In RCT, excess cholesterol from macrophage foam cells is transferred and carried by HDL to the liver for excretion as bile acids or free cholesterol into the feces, including ApoA1-activated LCAT-mediated HDL maturation, HDL cholesterol uptake via SR-BI, and biliary cholesterol secretion by ABCG5 and ABCG8 [38].…”

A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Infers How Plant Sterol Intake Reduces Circulating Cholesterol Levels

“…independently translocate cholesterol [29,64] by accepting cholesterol from the cytosol and unstirred water layer, respectively (Figure 1b). With recent evidence, we reconsidered the roles of the two transporters, as described below and depicted in Figure 1c.…”