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How does oxidized cholesterol interact with scavenger receptors?
Oxidized cholesterol plays a great role in the development of atherosclerosis by binding with scavenger receptors, which are present on macrophages. The way the binding takes place is as follows:
Cholesterol Oxidation: Cholesterol in lipoproteins (like low-density lipoproteins, or LDL) can be oxidized by exposure to free radicals or other oxidative stress. The oxidized form of cholesterol is more atherogenic than the non-oxidized form.
Scavenger Receptors: Scavenger receptors are a family of receptors that exist on the cell surface of macrophage immune cells. Their function is to recognize and internalize many forms of altered molecules, including oxidized LDL (oxLDL).
Identification of Oxidized Cholesterol: Oxidized cholesterol is identified by scavenger receptors such as SR-A (scavenger receptor class A) and CD36, present in LDL particles. Unlike the LDL receptor, however, scavenger receptors are not regulating uptake as a function of cholesterol quantity or oxidized moiety presence. The result is that there is an unremitting uptake of oxidized cholesterol by macrophages.
Formation of Foam Cells: When macrophages engulf oxidized LDL, the cholesterol is trapped in the form of lipid droplets, which convert the macrophages into foam cells. Foam cells are the hallmark of the formation of atherosclerotic plaque. Due to the deposition of foam cells with the progress of time, the arterial walls become thick and hardened.
Inflammation and Plaque Formation: The internalization of oxidized cholesterol also triggers inflammatory responses. Macrophages release cytokines and other pro-inflammatory substances, which enhance the development of atherosclerotic plaques. Inflammation also enhances the deposition of fatty material in the arteries, which goes on to advance the development of cardiovascular conditions like coronary artery disease.
In summary, the interaction of oxidized cholesterol with scavenger receptors on macrophages promotes the uptake of oxidized LDL, leading to foam cell formation and atherosclerotic plaque development, hence contributing to cardiovascular disease.
Oxidized cholesterol, particularly oxidized low-density lipoprotein (oxLDL), plays an important role in LDL receptor impairment, which is responsible for unsuccessful clearance of cholesterol and the genesis of atherosclerosis. An overview of impaired LDL receptor function by oxidized cholesterol is discussed below:
1. Oxidized Cholesterol and LDL Receptor Internalization
The LDL receptor (LDLR) primarily mediates the binding and uptake of native LDL and delivers it to cells within the liver where it is subject to processing and elimination.
When LDL is oxidized (oxLDL), it experiences conformational changes which alter its interaction with the LDL receptor. These changes decrease the likelihood of clearing oxLDL by the LDLR.
2. Reduced LDL Receptor Expression
Oxidized cholesterol can affect the expression of LDL receptors on the cell surface:
Inflammatory stimuli triggered by oxLDL downregulate the expression of LDL receptors, reducing the capacity of cells (specifically liver cells) to remove LDL from the bloodstream.
This is feedback in which inflammatory processes are activated by oxidized lipids to further inhibit the production of LDL receptors and resulting in a vicious cycle of increased LDL cholesterol in the blood.
3. Activation of Scavenger Receptors
Macrophages, which engulf oxLDL, rely on scavenger receptors (e.g., SR-A1, CD36) but not the LDL receptor to accumulate oxidized lipoproteins.
As a result, when the LDL is oxidized, these scavenger receptors are utilized by the macrophages preferentially for internalization. This is not only outside the LDLR pathway but it also leads to foam cell and plaque formation in the arteries causing atherosclerosis.
4. Disturbed Lipid Metabolism and Cholesterol Homeostasis
Oxidized cholesterol can affect lipid metabolism and lead to increased levels of cholesterol in the blood.
Reduced activity of LDL receptors, as well as tissue deposition of oxLDL, leads to disrupted cholesterol homeostasis. The organism will attempt to compensate for the perceived lack of cholesterol absorption by increasing hepatic cholesterol synthesis or by inducing lipid storage in arterial walls.
5. Defective Cholesterol Efflux and Reverse Cholesterol Transport
Cholesterol efflux refers to the process of cholesterol removal from cells and return to the liver for excretion. Oxidized cholesterol may hinder this process by changing the capacity of cholesterol efflux transporters such as ABCA1.
This malfunction contributes to the build-up of cholesterol in the vascular endothelium and supports the formation of atherosclerotic plaques.
Summary of the Role of Oxidized Cholesterol in LDL Receptor Dysfunction
Oxidized cholesterol (in oxLDL) causes dysfunction of the LDL receptor by decreasing its ability to recognize and engulf LDL. This leads to elevated circulating cholesterol and promotes foam cell formation in arteries, which plays a role in the development of atherosclerosis and cardiovascular disease. Oxidized cholesterol also causes inflammatory signals that suppress expression of the LDL receptor, further contributing to increased cholesterol deposition and plaque formation.
Would you like to know more about some of the signaling pathways or potential therapeutic possibilities to restore LDL receptors to function?
Ironbound™ A Strategy For The Management Of Hemochromatosis By Shelly Manning if you are suffering from the problems caused by the health condition of HCT due to excess amount of iron in your body then instead of using harmful chemical-based drugs and medications you are recommended to follow the program offered in Ironbound Shelly Manning, an eBook. In this eBook, she has discussed 5 superfoods and other methods to help you in reducing the level of iron in your body in a natural manner. Many people are benefited from this program after following it consistently.