The metabolism of lipoproteins can be divided into an exogenous and an endogenous pathway, which are connected through the liver (Fig. 1).

Fig1. Lipoprotein metabolism. IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein (Copyright EDISES 2021. Reproduced with permission)

 Exogenous Pathway of Lipid Metabolism

 The exogenous pathway of lipoprotein metabolism begins in the intestine, where dietary triglycerides (about 100 g/day) are hydrolyzed into fatty acids and monoacylglycerol by intestinal lipases and emulsified with bile acids, cholesterol, and fat-soluble vitamins to form micelles. The latter are then transported into the enterocytes, where cholesterol is esterified by the enzyme ACAT, while fatty acids and monoacylglycerol are converted into triglycerides. In the endoplasmic reticulum, triglycerides and cholesterol esters are “packed” into chylomicrons to be secreted into the lymphatic circulation and, later released, through the thoracic duct, into the systemic circulation. In the capillaries of the adipose and muscular tissue, LPL hydrolyses the triglycerides carried by the chylomicrons into glycerol and fatty acids. The latter are picked up by skeletal and cardiac muscle cells for energy production (beta-oxidation) and by adipocytes, where they are used as substrates for triglyceride synthesis and subsequent accumulation as an energy reserve.

Following the lipolytic activity of the LPL, the core of the chylomicrons, which is rich in triglycerides, condenses, resulting in excess of components of the outer structure (nonesterified cholesterol, phospholipids, ApoA-I, and ApoA-II), which are transferred to the nascent HDLs, from which they receive ApoE and ApoC. As a result of these modifications and the reduction in triglyceride content, chylomicrons transform into chylomicron remnants. ApoE plays a key role in mediating the interaction of chylomicron remnants with the LDL receptor expressed on hepatocytes, where these particles will be degraded. Mutations in the ApoE gene (e.g., the ApoE2 isoform) may result in reduced clearance of chylomicrons and increased plasma levels of cholesterol and triglycerides, a condition known as familial dysbetalipoproteinemia. In the liver, cholesterol can be used for the VLDL synthesis to it can be excreted in the bile as such or after transformation into bile acids and then released in the intestine.

Endogenous Pathway of Lipid Metabolism

In the liver, triglycerides and cholesterol are released into the systemic circulation as VLDLs. VLDL assembly is initiated by microsomal transfer protein (MTP), which trans ports lipids to ApoB-100. MTP mobilizes esterified cholesterol, triglycerides, and phospholipids from the cytosolic pool to lipoproteins forming in the endoplasmic reticulum. Mutations involving loss of function of ApoB-100 fall to produce VLDL and a marked reduction in circulating cholesterol and triglycerides (familial hypobetalipoproteinemia or abetalipoproteinemia).

Similar to chylomicrons, circulating VLDLs are exposed to the action of the LPL of adipose and muscle tissue capillaries which, by hydrolyzing the triglyceride-rich core, increases the esterified cholesterol content and transforms the particles making them smaller and denser; the excess sur face components (nonesterified cholesterol, phospholipids, apolipoproteins) are transferred to HDLs. In this way, VLDL is transformed into IDL.

A portion of IDL (about half) is reuptake by the liver through the interaction between ApoE (expressed on IDL) and the LDL receptor expressed on hepatocytes; the remaining portion undergoes further triglyceride hydrolysis by hepatic lipase, leading to the formation of LDL, consisting mainly of esterified cholesterol and ApoB-100.

LDLs have the role of transporting cholesterol to peripheral tissues, where they regulate both de novo synthesis and cholesterol uptake. Approximately two-thirds of LDL are removed from the circulation by such mechanism, which involves the internalization of particles following their inter action with R-LDL; the remaining portion is incorporated within the vascular wall where, by binding to proteoglycans, it becomes susceptible to modifications, such as oxidation. Oxidized LDLs are recognized and phagocytized by macro phages through interaction with scavenger receptors. This mechanism is the basis of the genesis of atheromatous plaques (Fig. 2).

Fig2. Mechanism of atherosclerotic plaque formation (Copyright EDISES 2021. Reproduced with permission)

Reverse Cholesterol Transport

Peripheral tissue cells accumulate cholesterol through the uptake of circulating lipoproteins or by de novo synthesis, but most do not possess a mechanism for the degradation of excess cholesterol. Cells synthesizing steroid hormones can convert cholesterol to glucocorticoids, estrogen, testosterone, etc.; intestinal cells can secrete cholesterol into the intestinal lumen. Most cells reduce their cholesterol content through reverse transport, mediated by HDLs, which return cholesterol to the liver. Specifically, HDLs pick up cholesterol in free form from peripheral tissue cells and release it in the esterified form to the liver, where it can be recycled to synthesize new lipoproteins, excreted in bile as free cholesterol, or eliminated as bile acids.

The first step (Fig. 3) in the reverse transport of cholesterol is the secretion by the gut and liver of pre-beta HDLs, consisting mainly of ApoA-I and small amounts of cholesterol and phospholipids (about 10%). Pre-beta HDLs represent initial acceptors of free cholesterol from cells. The membrane transporter ABCA1 plays a key role in mediating the efflux of free cholesterol from peripheral tissue cells to native HDLs, where the plasma enzyme LCAT mediates the esterification of the incorporated cholesterol, thereby transforming pre-beta HDLs into mature HDLs. The efficiency of reverse cholesterol transport depends primarily on the ability of ApoA-I to promote cholesterol efflux through interaction with ABCA1 and activate the LCAT enzyme.

Fig3. Reverse transport of cholesterol. HDLs are released by the liver and intestine in an immature form, known as pre-beta HDL, or nascent HDL, consisting of ApoA-I, free cholesterol, and phospholipids. Peripheral tissues and macrophages yield free cholesterol to nascent HDL while VLDL and chylomicrons yield triglycerides and apoproteins (ApoC-II, ApoE). Free cholesterol is esterified by the LCAT enzyme associated with HDL, thus leading to the formation of mature HDL. The latter can release the esterified cholesterol directly to the liver, through the interaction with SR-B1, or indirectly, through the action of CETP (cholesterol ester transfer protein), giving up the esterified cholesterol, in exchange of triglycerides, VLDLs and chylomicrons. HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; SR-B1, class B type 1 scavenger receptor; TG, triglycerides; VLDL, very low-density lipoprotein (Copyright EDISES 2021. Reproduced with permission)

Mature HDL releases esterified cholesterol to the liver primarily through two pathways, direct and indirect. 

In the direct pathway, SR-B1 receptor, expressed on the surface of hepatocytes, mediates the HDL interaction and modification by selectively removing cholesterol from mature HDL, and thus transforming them into lipid-poor HDL remnants, ready for a new cycle.

In the indirect pathway, circulating HDL, through the action of the CETP enzyme, releases cholesterol to ApoB- containing lipoproteins (VLDL and LDL), which are subsequently captured and degraded in the liver.

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Dyslipidemia and Cardiovascular Risk

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Metabolic Pathways at The Organ & Cellular Level

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