Attenuating lipid metabolism in atherosclerosis: The potential role of Anti-oxidative effects on low-density lipoprotein of herbal medicines

Abstract

Atherosclerosis (AS) is a multifactorial chronic disease with great harm to the health of human being, which is a basic pathogenesis of many cardiovascular diseases and ultimately threatens human life. Abnormal blood lipid level is one of the most common diagnostic indicators of AS in clinic, and lipid metabolism disorder is often observed in patients with AS. Cholesterol is an important lipid in the human body, which is of great significance for maintaining normal life activities. Generally, cholesterol is transported to peripheral tissues by low-density lipoprotein (LDL), and then transported to the liver by high-density lipoprotein (HDL) via its cholesterol reverse transport function, and finally discharged. Under oxidative stress condition, LDL is commonly oxidized to the form ox-LDL, which is ingested by macrophages in large quantities and further forms foam cells, disrupting the normal metabolic process of cholesterol. Importantly, the foam cells are involved in forming atherosclerotic plaques, whose rupture may lead to ischemic heart disease or stroke. Furthermore, ox-LDL could also promote the development of AS by damaging vascular endothelium, promoting the migration and proliferation of smooth muscle cells, and activating platelets. Therefore, inhibiting LDL oxidation may be an effective way to improve lipid metabolism and prevent AS. In recent years, increasing studies have shown that herbal medicines have great potentiality in inhibiting LDL oxidation and reducing ox-LDL induced foam cell formation. Accordingly, this paper summarized current research on the inhibitory effects of herbal medicines against LDL oxidation and foam cell formation, and made a brief description of the role of cholesterol and LDL in lipid metabolism disorder and AS pathogenesis. Importantly, it is suggested that herbal medicines could inhibit LDL oxidation and regulate cholesterol homeostasis via downregulation of CD36 and SR-A, whereas upregulation of ABCA1 and ABCG1.

Keywords: atherosclerosis; herbal medicines; lipid metabolism; low-density lipoprotein; oxidative stress.

FIGURE 1

Structure and formation of LDL. (A) A single LDL particle is composed of phospholipids, unesterified cholesterol and Apo B in the outer layer, and cholesterol esters and triglycerides in the inner layer. (B) CM mainly consists of dietary fat and several kinds of apolipoprotein, including Apo B48, Apo A, Apo C, and Apo E. It is generated on the intestinal mucosa, and then hydrolyzed into chyle particles in the intestine, which will form VLDL with Apo B100. Consequently, TG in VLDL is partially hydrolyzed, as well as losing Apo C and Apo E to be converted into LDL.

FIGURE 2

Role of LDL and HDL in cholesterol metabolism. Dietary cholesterol ingested from food enters enterocyte under the mediation of NPC1L1 and forms CM. After being released into blood, CM is gradually converted into VLDL, and then further converted into LDL, which is absorbed by liver under the mediation of LDLR. Some of the cholesterol in the liver is esterified to form cholesterol ester to form VLDL which will be released into blood, while the other part enters intestinal lumen/bile duct to be reabsorbed into the circulation or excreted from the body. In addition, the free cholesterol transferred to plasma under the mediation of ABCA1 combines with apoA-I to form nascent HDL, which is absorbed by liver through SR-BI to complete the reverse cholesterol transport.

FIGURE 3

The oxidative modification of LDL. Under oxidative stress condition, phospholipids and Apo B100 in the outer layer of LDL are oxidized, and the lysine residues of Apo B100 reacted with reactive aldehydes from oxidative phospholipids to form Schiff base. Then, the cholesterol ester in the inner layer of LDL is gradually oxidized with the oxidation rate is as high as 90%.

FIGURE 4

The role of ox-LDL in cholesterol metabolism and foam cell formation. LDL passes through the damaged endothelium, where it is oxidized by ROS and then converts to ox-LDL, interacting with macrophage-derived monocytes. During this process, the expression of CD36, SR-A1, and LOX-1 on the surface of macrophages is upregulated, while the expression of receptors that mediate cholesterol reverse transport is downregulated, including ABCA1, ABCG1, and SR-B1. As a result, cholesterol in macrophages accumulates and eventually foam cells are formed. However, many herbal medicines can reduce the accumulation of cholesterol and inhibit the formation of foam cells by inhibiting the oxidative modification of LDL.