BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E.S. Severin - 2004

CHAPTER 8. LIPID METABOLISM

III. Transport of Dietary Fats from the Intestine by Chylomicrons

Lipids are insoluble in an aqueous environment (and consequently in Blood); therefore, to facilitate their transport through the bloodstream, the body forms lipid-Structure/178.html">Protein Complexes known as Lipoproteins.

A. General characteristics of Lipoproteins

All lipoprotein classes share a similar architecture, consisting of a Hydrophobic core surrounded by a hydrophilic surface monolayer (Fig. 8-18). This outer shell is composed of Proteins, termed apoproteins, along with amphiphilic lipid molecules—specifically Phospholipids and Cholesterol. The hydrophilic HEAD groups of these molecules face the aqueous phase, whereas their hydrophobic tails project inward toward the lipid core, which houses the transported lipids. Certain apoproteins are integral and cannot be dissociated from the lipoprotein, whereas others freely exchange between different lipoprotein classes. Apoproteins fulfill several key Functions:

✵ they stabilize the structural integrity of lipoproteins;

✵ they interact with Cell-surface receptors, thereby determining which Tissues will uptake a given Class of lipoproteins; and

✵ they act as Enzymes or as enzymatic activators that modulate lipoprotein METABOLISM.

Fig. 8-18. Plasma lipoproteins.

The body synthesizes several distinct classes of lipoproteins (see Table 8-5 below): chylomicrons (CM), very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).

Each lipoprotein class is produced in specific tissues and transports distinct types of lipids. For instance, CMs transport exogenous (dietary) fats from the intestines to peripheral tissues, meaning that triacylglycerols account for up to 85% of their mass.

Lipoproteins are highly soluble in blood and do not coalesce, owing to their small size and net negative surface charge. Furthermore, certain lipoproteins readily cross capillary walls to deliver lipids directly to Cells.

Because of their large size, chylomicrons are unable to cross capillary walls; instead, they first enter The Lymphatic system from intestinal epithelial cells and subsequently reach the bloodstream via the Thoracic duct, mixing with the Lymph.

Research Methods. The composition of plasma lipoproteins can be analyzed using various techniques (Fig. 8-19). Ultracentrifugation separates lipoproteins based on differences in their buoyant density, which is determined by the lipid-to-protein ratio of the particles. Because fat has a lower density than Water, CMs—containing over 85% lipid—float to the top of blood serum, whereas HDLs, possessing the highest protein content and greatest density, sediment at the bottom of the centrifuge tube. Since lipoproteins were first isolated from blood serum via ultracentrifugation, their nomenclature reflects their particle density. However, because ultracentrifugation is impractical for routine clinical use, clinical laboratories typically rely on Electrophoresis. The electrophoretic mobility of these particles depends on both their charge and size. Surface charge, in turn, is governed by The amount of protein associated with the lipoprotein (Table 8-5). During gel electrophoresis, all lipoprotein classes migrate toward the positive electrode: CMs remain near the origin, whereas HDLs, possessing the highest protein content and smallest size, migrate the farthest from the origin.

The composition of blood lipoproteins fluctuates significantly throughout the day. During the absorptive phase (particularly following a high-fat meal), chylomicrons appear in the Circulation. Carbohydrate-rich meals promote the synthesis of VLDLs, as these particles transport fats synthesized in the Liver from excess CARBOHYDRATES. In the post-absorptive state and during fasting, only LDLs and HDLs are present in the blood, their primary function being cholesterol transport.

B. Formation of Chylomicrons

Fats resynthesized within the Cells of the intestinal mucosa are packaged into chylomicrons. The primary apoprotein of CMs is apolipoprotein B-48 (apoB-48). This protein is encoded by the same Gene as the VLDL-associated protein apoB-100 (Table 8-5), which is synthesized in the liver. Within the intestinal epithelium, post-transcriptional RNA editing introduces a premature stop codon that reads only 48% of the apoB-100 mRNA transcript, giving rise to apoB-48. ApoB-48 is synthesized in the rough Endoplasmic reticulum (RER), where it also undergoes initial glycosylation. Subsequently, nascent chylomicrons are assembled within the Golgi apparatus. They are then secreted via exocytosis into the lacteals of the intestinal villi, entering the bloodstream through the thoracic duct. In both the lymph and the blood, HDL particles transfer apolipoproteins E (apoE) and C-II (apoC-II) to the nascent CMs, converting them into mature chylomicrons. Because CMs are relatively large, they impart an opalescent, milk-like appearance to Blood Plasma following a fat-rich meal. As CMs transport dietary fat to various peripheral tissues for utilization, their concentration in the blood gradually declines, and the plasma clears once more. Chylomicrons are entirely cleared from the bloodstream within several hours.

Table 8-5. Lipoproteins as Lipid Transport Vehicles

Notes: PL — phospholipids; Chol — cholesterol; CE — cholesteryl esters; TAG — triacylglycerols. Functions of apoproteins:

✵ B-48 — major structural protein of chylomicrons;

✵ B-100 — major structural protein of VLDL, LDL, and IDL; interacts with LDL receptors;

✵ C-II — activator of lipoprotein lipase; transferred from HDL to CM and VLDL within the bloodstream;

✵ E — interacts with LDL receptors;

✵ A-I — activator of the enzyme lecithin-cholesterol acyltransferase (LCAT).

A rare hereditary disorder—apolipoprotein B gene defect—disrupts the synthesis of apoB-100 proteins in The Liver and apoB-48 in the intestine. As a result, chylomicrons (CMs) fail to form in the intestinal mucosal cells, and VLDLs fail to form in the liver. Fat droplets accumulate within the cells of these Organs. This condition is called abetalipoproteinemia, as VLDLs are alternatively known as pre-β-lipoproteins.

Fig. 8-19. Separation of serum lipoproteins. A — ultracentrifugation method. B — Polyacrylamide gel electrophoresis method 2 h after a meal.

B. Utilization of exogenous fats by tissues

Action of lipoprotein lipase on CMs. In the blood, triacylglycerols within mature CMs are hydrolyzed by the enzyme lipoprotein lipase, or LPL (Fig. 8-20). LPL is bound to heparan sulfate (a heteropolysaccharide) located On the surface of endothelial cells lining the walls of blood capillaries. LPL hydrolyzes fat molecules into glycerol and 3 fatty acid molecules. Two factors necessary for LPL activity are identified on The surface of CMs: apoC-II and phospholipids. ApoC-II activates this enzyme, while phospholipids participate in binding the enzyme to the CM surface.

LPL is synthesized in the cells of many tissues: adipose tissue, Muscle, Lungs, Spleen, and Cytology/practical/135.html">Lactating mammary gland cells. LPL isozymes in different tissues differ in their K_m values: adipose tissue LPL has a K_m value 10 times higher than that of Heart LPL, for example; therefore, the Hydrolysis of CM fats in adipose tissue occurs during the absorptive period. Fatty acids enter adipocytes and are utilized for fat synthesis. In the postabsorptive state, when blood fat levels decline, heart muscle LPL continues to hydrolyze fats within VLDLs, which are present in the blood in small quantities, and Fatty acids are utilized by this tissue as Energy Sources even at low blood fat concentrations. LPL is absent in the liver, but another enzyme is present on The Cell surface of this organ—hepatic lipase, which does not act on mature CMs but hydrolyzes fats in IDLs formed from VLDLs.

Fate of fatty acids, glycerol, and remnant chylomicrons. As a result of LPL action on CM fats, Fatty Acids and glycerol are formed. The bulk of the fatty acids enters tissues (Fig. 8-20). In adipose tissue during the absorptive period, fatty acids are stored as triacylglycerols; in heart muscle and working skeletal Muscles, they are used as an energy source. Another fat hydrolysis product, glycerol, is soluble in the blood and transported to the liver, where it can be utilized for fat synthesis during the absorptive period.

Fig. 8-20. Pathway of exogenous fats and chylomicrons. *LPL — lipoprotein lipase, FAs — fatty acids.

As a result of LPL action on CMs, their fat content decreases by 90%, particle size diminishes, and apolipoprotein C-II is transferred back to HDLs. The resulting particles are called remnant CMs. They contain phospholipids, cholesterol, Fat-soluble Vitamins, and apolipoproteins B-48 and E. Remnant CMs are taken up by hepatocytes, which possess receptors that interact with these apolipoproteins. Through endocytosis, remnant CMs enter the cells, where lysosomal enzymes hydrolyze the proteins and lipids, which are then utilized. Fat-soluble vitamins and exogenous cholesterol are used in the liver or transported to other tissues.

Hyperchylomicronemia, hypertriglyceridemia. Following the ingestion of a fat-containing meal, physiological hypertriglyceridemia and, accordingly, hyperchylomicronemia develop, which can persist for up to several hours.

The rate of CM clearance from the bloodstream depends on:

✵ LPL activity;

✵ the presence of HDLs supplying apo-proteins C-II and E for CMs;

✵ the rate of apoC-II and apoE transfer to CMs.

Genetic Defects in any of the proteins involved in CM metabolism lead to The Development of familial hyperchylomicronemia—type I hyperlipoproteinemia. In such patients, the triacylglycerol concentration is elevated in the postabsorptive period (exceeding 200 mg/dL), blood plasma has a milk-like appearance, and upon standing in the cold (+4 °C), white fatty flakes rise to the surface, which is characteristic of hypertriglyceridemia and hyperchylomicronemia.

In severe cases of this disorder, triacylglycerols are deposited in the Skin and tendons as xanthomas, patients experience early memory impairment, abdominal pain due to vascular lumen narrowing and reduced blood flow, and pancreatic dysfunction, which is often the cause of patient death. If the blood triacylglycerol concentration exceeds 4000 mg/dL, lipids are deposited in the retina, although this does not always impair visual function. The Treatment of hyperchylomicroneia primarily requires reducing dietary fat intake, since CMs transport exogenous fats.