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![ABSORPTION OF DIETARY LIPID
lumen
• Dietary fats are emulsified in the SI- action of
bile acid.
• Lipids and bile salts interact to form
micelles[4-8 nanometer] -contain FA,
monoglycerides & C in their
hydrophobic centers.
• Micelles solubilizes the lipids and provides a
mechanism for their transport
to the enterocytes.](https://image.slidesharecdn.com/lipoprmetabolism-170223084739/85/Lipoprotein-metabolism-9-320.jpg)
![enterocyte
• TAG-DAG transferase converts FFA+MAG again
in to TAG(occurs in SER)
• MTP facilitates transfer of TAG to the site –
apoB48
• CHOLESTEROL- is converted to CE by ACAT-
2(I&L).[ACAT1 in macrophage]
• NASCENT CHYLOMICRON-TAG is combined
with PL, CE,apoB48- exocytosed-lacteals-
thoracic duct-systemic circulation](https://image.slidesharecdn.com/lipoprmetabolism-170223084739/85/Lipoprotein-metabolism-11-320.jpg)
![CHYLOMICRON REMNANT
• CM- metabolized at capillary luminal surface - LPL [ adipose tissue, skel.
&cardiac m, breast tissue -lactating women].
• TAG -hydrolyzed by LPL(apoC2-cofactor)-FFA utilized by adjacent tissues.
Glycerol-in liver(glycolysis,gluconeogenesis)
• CM remnants- still contain dietary C- detach from the capillary.
• Remnants - sequestered by the interaction of apoE -heparan sulfate
proteoglycans - surface of hepatocytes & processed by hepatic lipase,
further reducing the remnant TAG content.
• ApoE mediates remnant uptake by interacting with the hepatic LDL
receptor or LRP.
• LRP - backup R- uptake of apoE-enriched remnants of CM and VLDL. HSP,
facilitate the interaction of apoE-containing remnant LP with the LRP.
• Initial hydrolysis of CM - apoA-I and PL shed from the surface of CM in the
plasma-(nascent HDL)](https://image.slidesharecdn.com/lipoprmetabolism-170223084739/85/Lipoprotein-metabolism-16-320.jpg)
![LDL
• TAG in plasma VLDL- hydrolysed by LPL in
capillary endothelium- IDL [<30% TAG]
• ApoB-100 containing small VLDL and IDL (VLDL
remnants), 2 potential fates
• 40-60%- cleared from the plasma by liver via
interaction with LDL receptors & LRP.
• LPL and HL convert remainder of IDL to
[TG<10%]LDL . The apo E,C, redistribute to HDL.](https://image.slidesharecdn.com/lipoprmetabolism-170223084739/85/Lipoprotein-metabolism-22-320.jpg)
![NASCENT CHYLOMICRON
• CM are assembled in intestinal mucosal cells and carry
dietary TAG,cholesterol, fat-sol. vit, and CE [TAGs 90%]
•
• Apolipoprotein B-48 is unique to chylomicrons. Its synthesis
begins on the RER.
• The enzymes involved in TAG, cholesterol, and PL synthesis
are located in the SER. Assembly of the apo and lipid into
CM requires MTP.
• The particle released by the intestinal mucosal cell is called
a “nascent” chylomicron because it is functionally
incomplete.](https://image.slidesharecdn.com/lipoprmetabolism-170223084739/85/Lipoprotein-metabolism-44-320.jpg)
More Related Content
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Lipoprotein metabolism,
- 1. LIPOPROTEIN METABOLISM Dr ANKITAMISHRA JNMCH AMU,ALIGARH
- 2. LIPOPROTEIN • Macromolecular assembly thatcontain lipids and proteins.
- 3.
- 4. APOPROTEINS • Surface proteinspresent on lipoproteins. • Functions • Provides structural stability to lipoproteins. • Ligands in lipoprotein-receptor interactions. • Cofactors in enzymatic processes that regulate lipoprotein metabolism. • 2 types • Integral proteins- Peripheral proteins- Apo A & B Apo C & E
- 5. Apo A1- L,IHDL,LCAT cofactor,ABCA1 ligand Apo A2- L inhibits apoE binding to R Apo A5- L activates LPL, inhibit VLDL TAG Apo B100-L struc. Pr. ,LDL R ligand Apo B48- I struc. Pr. CM Apo C1- L LCAT activator,R binding -remnant Apo C2- L LPL cofactor Apo C3- L R binding of remnant Apo E- L,B,G,S ligand LDL R,remnant R Apo (a)- L modulator of fibrinolysis
- 6. LIPOPROTEIN METABOLISM 1.Transport ofexogenous (dietary)lipids (chylomicron processing) 2.Transport of endogenous lipids Apo B-100 lipoprotein guided system Apo A1 governed lipoprotein system
- 7. TRANSPORT OF EXOGENOUSLIPIDS • ABSORPTION OF DIETARY LIPIDS • NASCENT CHYLOMICRON • CHYLOMICRON • CHYLOMICRON REMNANTS
- 8. ABSORPTION OF DIETARYLIPID • In order for the dietary lipids to be absorbed 1. large aggregate,must be broken down physically and held in suspension-emulsification 2. TAG –enzymatically digested to yield - MAG & Fatty acids- easily diffuse in to the enterocytes. • 2 key players in this transformation-Bile acid & Pancreatic lipase
- 9. ABSORPTION OF DIETARYLIPID lumen • Dietary fats are emulsified in the SI- action of bile acid. • Lipids and bile salts interact to form micelles[4-8 nanometer] -contain FA, monoglycerides & C in their hydrophobic centers. • Micelles solubilizes the lipids and provides a mechanism for their transport to the enterocytes.
- 10. Lumen-enterocyte TAG -Pancreatic lipase actson TAG in micelle-- MAG & FFA- taken up by enterocyte -Short chain& medium chain FFA are absorbed directly in to the enterocytes and then to portal circulation. CHOLESTEROL -NPC1L1mediatesabsorption of intest. C,plant sterol. -C taken up by enterocytes in micellar form. -Plant sterols are notabsorbed. -ABCG5&8 transporters - channel plant sterol back in to the lumen.
- 11. enterocyte • TAG-DAG transferaseconverts FFA+MAG again in to TAG(occurs in SER) • MTP facilitates transfer of TAG to the site – apoB48 • CHOLESTEROL- is converted to CE by ACAT- 2(I&L).[ACAT1 in macrophage] • NASCENT CHYLOMICRON-TAG is combined with PL, CE,apoB48- exocytosed-lacteals- thoracic duct-systemic circulation
- 12. Micelles,C Niemann Pick C1like Protein (NPC1 LP) Triglycerides Microsomal Transfer Protein (MTP) ER Apo B-48 Chylomicron Cholesterol Cholesterol Esters ACAT-2 (Acyl Coenzyme A: Cholesterol Acyl Transferase)
- 13. DIET TAG, CHOLESTEROL ,FAT SOL. VITAMIN FA+GLYCEROL TAG + CE + APO B48,A1 + PL NASCENT CHYLOMICRON ACAT2DAG LIPASE
- 14. CHYLOMICRON • NASCENT CMreaches the plasma-rapidly modified- receive apo E and C. • The source of these apolipoproteins is circulating HDL • This leads to formation of mature CHYLOMICRON.
- 15. NASCENT CHYLOMICRON THORACIC DUCT SYSTEMICCIRCULATION APO E,C(HDL) CHYLOMICRON Apo-A
- 16. CHYLOMICRON REMNANT • CM-metabolized at capillary luminal surface - LPL [ adipose tissue, skel. &cardiac m, breast tissue -lactating women]. • TAG -hydrolyzed by LPL(apoC2-cofactor)-FFA utilized by adjacent tissues. Glycerol-in liver(glycolysis,gluconeogenesis) • CM remnants- still contain dietary C- detach from the capillary. • Remnants - sequestered by the interaction of apoE -heparan sulfate proteoglycans - surface of hepatocytes & processed by hepatic lipase, further reducing the remnant TAG content. • ApoE mediates remnant uptake by interacting with the hepatic LDL receptor or LRP. • LRP - backup R- uptake of apoE-enriched remnants of CM and VLDL. HSP, facilitate the interaction of apoE-containing remnant LP with the LRP. • Initial hydrolysis of CM - apoA-I and PL shed from the surface of CM in the plasma-(nascent HDL)
- 17.
- 18. Cholesterol biosynthesis Acetyl CoAAcetoacetyl CoA HMG- CoA Hydorxy Methyl Glutarate HMG- CoA Reductase Mevalonate Presqualena Pyrophosphate Squalene Squalene synthase Cholesterol
- 19.
- 20. VLDL • VLDL areproduced in the liver when TAG production is stimulated by an increased flux of FFA / increased de novo synthesis of FA by the liver. • ApoB-100 , synthesized in liver -incorporated into VLDL . Small amounts of apoE & C are incorporated into nascent VLDL (TAG approx 60% )within liver before secretion. • most of the apoE & C are acquired from plasma HDL after VLDL are secreted by the liver
- 21. FFA TAG NASCENT VLDL APO B100,,E,C VLDL APOE,C(HDL) LIVER PLASMA APOB100 APO-E APO-C
- 22. LDL • TAG inplasma VLDL- hydrolysed by LPL in capillary endothelium- IDL [<30% TAG] • ApoB-100 containing small VLDL and IDL (VLDL remnants), 2 potential fates • 40-60%- cleared from the plasma by liver via interaction with LDL receptors & LRP. • LPL and HL convert remainder of IDL to [TG<10%]LDL . The apo E,C, redistribute to HDL.
- 23. VLDL IDL TG FFA LPL LPL LDL TG APO C,E(HDL) APO-B100 CHOLESTEROL CELLMEMBRANE VIT D MYELIN SHEATH STEROID HORMONE
- 24. REGULATION OF CHOLESTEROLSYNTH. • Liver expresses a large complement of LDL R & removes 75% of LDL from plasma- manipulation of hepatic LDL R gene expression is most effective way to modulate plasma LDL-C levels. • Regulation of LDL receptor expression- part of complex process by which cells regulate their free C content.- transcription factors - sterol regulatory element binding proteins (SREBPs) and SREBP cleavage activating protein (Scap) . • Scap- a sensor of C content in ER & an escort of SREBPs from ER to Golgi apparatus. • In Golgi - SREBPs undergo proteolytic cleavage-nucleus- it activates expression of the LDL R gene & of genes encoding enzymes involved in C biosynthesis. • ER C content binds Scap, precluding Scap from escorting SREBP to the Golgi A for processing & ultimately from reaching the nucleus.
- 25. ROLE OF LDLIN ATHEROGENESIS
- 26. HDL • FUNCTIONS • Servesas a circulating reservoir for apo-C and apo-E. • Delivering-chol. esters to liver for uptake by SR-B1(reverse cholesterol transport). • Protective effect - anti-inflammatory, anti- oxidative, platelet anti-aggregatory, anticoagulant, and profibrinolytic activities
- 28. HDL METABOLISM • Theprecursor HDL is a discoidal particle containing apoA-I &PL called preβ-1 HDL . • Synthesized by liver &intestine, & also arise when surface PL & apoA-I of CM and VLDL are lost as the TAG of these LP are hydrolyzed. • Discoidal pre-β1 HDL - acquire free C from tissues, macrophages. ABCA1 and ABCG1, promote the efflux of C from macrophages . • The membrane transporter ABCA1 facilitates the transfer of free C from cells to HDL . • Free C esterified by LCAT.---Esterified &nonpolar C moves into the core of the discoidal HDL.
- 29. Contd. • As theCE content increases, the HDL particle becomes spherical - HDL3 • further enlarge by accepting more free C which is in turn esterified by LCAT -HDL2 • As the CE content of the HDL2 increases, the CE of these particles begin to be exchanged for TAG derived from any of the TAG containing LP . This exchange is mediated by the CETP . • The transferred C -metabolized as part of the lipoprot • SR-B1 in liver facilitates uptake of CE from HDL. • HDL2 ,TAG is hydrolyzed by HL-regenerates - HDL3 - recirculate & acquire additional free C from tissues containing excess C.
- 31. LIPOPROTEIN (A) • Lp(a)is composed of an LDL particle that has a second apoprotein in addition to apoB-100 • Apo(a), is attached to apoB-100 by at least one disulfide bond • does not function as a lipid-binding apoprotein. • Apo(a) of Lp(a) is structurally related to plasminogen • Atherogenic - interferes with fibrinolysis of thrombi on the surfaces of plaques
- 32.
- 33.
- 35.
- 36.
- 37. LIPIDS • Heterogenous gp.of compounds related to fatty acids,insoluble in water & are stored in the body as source of energy. 3 types • Simple lipids-SSFAs,MUFAs,PUFAs,TFAs • Compound lipids-sulfolipids,phospholipids • Neutral lipids-TGs,CH,CE
- 39. Lipoproteins Lipoprotein Apoproteins Function ChylomicronapoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissues VLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles. IDL apoB-48, apoC, apoE Intermediary between VLDL and LDL LDL apoB-48 Transport cholesterol to peripheral tissues. HDL apoA, apoC, apoE, apoD •Absorb cholesterol form peripheral tissues and transport it to liver •Reservoir for exchange of lipoproteins in VLDL and Chylomicron metabolism
- 41. INTRODUCTION • Lipoprotein • Apoprotein •Lipoprotein metabolism • Dyslipidaemia • Metabolic syndrome
- 43.
- 44. NASCENT CHYLOMICRON • CMare assembled in intestinal mucosal cells and carry dietary TAG,cholesterol, fat-sol. vit, and CE [TAGs 90%] • • Apolipoprotein B-48 is unique to chylomicrons. Its synthesis begins on the RER. • The enzymes involved in TAG, cholesterol, and PL synthesis are located in the SER. Assembly of the apo and lipid into CM requires MTP. • The particle released by the intestinal mucosal cell is called a “nascent” chylomicron because it is functionally incomplete.
- 45. CHYLOMICRON REMNANT • TAGin CM core - degraded by LPL , the particle decreases in size and increases in density. • The apo C (but not apo E) are returned to HDL. The remaining particle, called a “remnant,” is rapidly removed from the circulation by the liver, whose cell membranes contain lipoprotein receptors that recognize apo E. • Chylomicron remnants are taken into the hepatocytes by endocytosis. The endocytosed vesicle fuses with a lysosome, and apo, C,E, and other components of the remnant are degraded, releasing amino acids, free cholesterol, and fatty acids.
- 49. METABOLISM OF HDL •Nascent HDL are discoidal phospholipid layer containing apo-A,C,E and free cholesterol. HDL is synthesized and secreted by both liver and intestine. LCAT binds to the discoidal HDL and converts the free cholesterol in to cholesteryl ester. The nonpolar cholesteryl ester move in to the hydrophobic core-as cholesteryl esters accumulate it becomes spherical HDL3 .
- 50. CONTD. • HDL2 issynthesized when more cholesterol is accepted by HDL3 from peripheral tissue. • CETP moves some of the CE from HDL to TAG containing lipoprotein and accepts TAG from them. • HDL3 then reforms either after selective delivery of CE to liver by SRB1 or by hydrolysis of TAG & PL by HL.This interchange of HDL2 & HDL3 is called HDL cycle. • Free apoA1 is released by these processes and form pre β HDL(nascent) after attaching with min. amt of PL and cholesterol.
- 51.
Editor's Notes
- #3 Lipoproteins are macromolecular assemblies that contain lipids and proteins. The lipid constituents include free and esterified cholesterol, triglycerides, and phospholipids. The protein components, known as apolipoproteins or apoproteins, provide structural stability to the lipoproteins and also may function as ligands in lipoprotein–receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism. In all spherical lipoproteins, the most water-insoluble lipids (cholesteryl esters and triglycerides) are core components, and the more polar, water-soluble components (apoproteins, phospholipids, and unesterified cholesterol) are located on the surface
- #6 ApoA-I 130 11 29 Liver, intestine Structural in HDL; LCAT cofactor; ligand of ABCA1 receptor; reverse cholesterol transport ApoA-II 40 1 17 Liver Forms –S–S–complex with apoE-2 and E-3, which inhibits E-2 and E-3 binding to lipoprotein receptors ApoA-V <1 11 40 Liver Modulates triglyceride incorporation into hepatic VLDL; activates LPL ApoB-100 85 2 513 Liver Structural protein of VLDL, IDL, LDL; LDL receptor ligand ApoB-48 Fluctuates according to dietary fat intake 2 241 Intestine Structural protein of chylomicrons ApoC-I 6 19 6.6 Liver LCAT activator; modulates receptor binding of remnants ApoC-II 3 19 8.9 Liver Lipoprotein lipase cofactor ApoC-III 12 11 8.8 Liver Modulates receptor binding of remnants ApoE 5 19 34 Liver, brain, skin, gonads, spleen Ligand for LDL receptor and receptors binding remnants; reverse cholesterol transport (HDL with apoE) Apo(a) Variable (under genetic control) 6 Variable Liver Modulator of fibrinolysis
- #10 A lingual lipase is secreted by Ebner's glands on the dorsal surface of the tongue in some species, and the stomach also secretes a lipase (Table 27–1). They are of little quantitative significance for lipid digestion other than in the setting of pancreatic insufficiency, however. Most fat digestion therefore begins in the duodenum, pancreatic lipase being one of the most important enzymes involved. This enzyme hydrolyzes the 1- and 3-bonds of the triglycerides (triacylglycerols) with relative ease but acts on the 2-bonds at a very low rate, so the principal products of its action are free fatty acids and 2-monoglycerides (2-monoacylglycerols). It acts on fats that have been emulsified (see below). Its activity is facilitated when an amphipathic helix that covers the active site like a lid is bent back. Colipase, a protein with a molecular weight of about 11,000, is also secreted in the pancreatic juice, and when this molecule binds to the –COOH-terminal domain of the pancreatic lipase, opening of the lid is facilitated. Colipase is secreted in an inactive proform (Table 27–1) and is activated in the intestinal lumen by trypsin. Another pancreatic lipase that is activated by bile salts has been characterized. This 100,000-kDa cholesterol esterase represents about 4% of the total protein in pancreatic juice. In adults, pancreatic lipase is 10–60 times more active, but unlike pancreatic lipase, this bile salt-activated lipase catalyzes the hydrolysis of cholesterol esters, esters of fat-soluble vitamins, and phospholipids, as well as triglycerides. A very similar enzyme is found in human milk. Fats are relatively insoluble, which limits their ability to cross the unstirred layer and reach the surface of the mucosal cells. However, they are finely emulsified in the small intestine by the detergent action of bile salts, lecithin, and monoglycerides. When the concentration of bile salts in the intestine is high, as it is after contraction of the gallbladder, lipids and bile salts interact spontaneously to form micelles (Figure 26–16). These cylindrical aggregates, which are discussed in more detail in Chapter 29, take up lipids, and although their lipid concentration varies, they generally contain fatty acids, monoglycerides, and cholesterol in their hydrophobic centers. Micellar formation further solubilizes the lipids and provides a mechanism for their transport to the enterocytes. Thus, the micelles move down their concentration gradient through the unstirred layer to the brush border of the mucosal cells. The lipids diffuse out of the micelles, and a saturated aqueous solution of the lipids is maintained in contact with the brush border of the mucosal cells (Figure 26–16).
- #11 Intestinal cholesterol and plant sterol absorption is mediated by Niemann-Pick C1–Like 1 protein (NPC1L1), which appears to be the target of ezetimibe, a cholesterol absorption inhibitor (Davis and Altmann, 2009). Plant sterols, unlike cholesterol, are not normally esterified and incorporated into chylomicrons. Two ATP-binding cassette (ABC) half-transporters, ABCG5 and ABCG8, which reside on the apical plasma membrane of enterocytes, channel plant sterols back into the intestinal lumen, preventing their assimilation into the body. Patients with the autosomal recessive disorder sitosterolemia have mutations in either of the genes that encode ABCG5 and ABCG8. As a result, they absorb unusually large amounts of plant sterols, fail to excrete dietary sterols into the bile, and thus accumulate plant sterols in the blood and tissues; this accumulation is associated with tendon and subcutaneous xanthomas and a markedly increased risk of premature CHD. Triglyceride synthesis is regulated by diacylglycerol transferase in many tissues. After their synthesis in the endoplasmic reticulum, triglycerides are transferred by microsomal triglyceride transfer protein (MTP) to the site where newly synthesized apoB-48 is available to form chylomicrons
- #12 The apolipoproteins of chylomicrons include some that are synthesized by intestinal epithelial cells (apoB-48, apoA-I, and apoA-IV), and others acquired from HDL (apoE and apoC-I, C-II, and C-III) after chylomicrons have been secreted into the lymph and enter the plasma (Table 31–2). The apoB-48 of chylomicrons is one of two forms of apoB present in lipoproteins. ApoB-48, synthesized only by intestinal epithelial cells, is unique to chylomicrons. ApoB-100 is synthesized by the liver and incorporated into VLDL and intermediate-density lipoproteins (IDL) and LDL, which are products of VLDL catabolism. The apparent molecular weight of apoB-48 is 48% that of apoB-100, which accounts for the name "apoB-48." The amino acid sequence of apoB-48 is identical to the first 2152 of the 4536 residues of apoB-100. An RNA-editing mechanism unique to the intestine accounts for the premature termination of the translation of the apoB-100 mRNA. ApoB-48 lacks the portion of the sequence of apoB-100 that allows apoB-100 to bind to the LDL receptor, so apoB-48 functions primarily as a structural component of chylomicrons. Dietary cholesterol is esterified by the type 2 isozyme of acyl coenzyme A:cholesterol acyltransferase (ACAT-2). ACAT-2 is found in the intestine and in the liver, where cellular free cholesterol is esterified before triglyceride-rich lipoproteins [chylomicrons and very-low-density lipoproteins (VLDL)] are assembled. In the intestine, ACAT-2 regulates the absorption of dietary cholesterol and thus may be a potential pharmacological target for reducing blood cholesterol levels. Another ACAT enzyme, ACAT-1, is expressed in macrophages, including foam cells, adrenocortical cells, and skin sebaceous glands. Although ACAT-1 esterifies cholesterol and promotes foam-cell development, ACAT-1 knockout mice do not have reduced susceptibility to atherosclerosis
- #15 After gaining entry to the circulation via the thoracic duct, chylomicrons are metabolized initially at the capillary luminal surface of tissues that synthesize lipoprotein lipase (LPL), a triglyceride hydrolase (Figure 31–1). These tissues include adipose tissue, skeletal and cardiac muscle, and breast tissue of lactating women. As the triglycerides are hydrolyzed by LPL, the resulting free fatty acids are taken up and utilized by the adjacent tissues. The interaction of chylomicrons and LPL requires apoC-II as an absolute cofactor. The absence of functional LPL or functional apoC-II prevents the hydrolysis of triglycerides in chylomicrons and results in severe hypertriglyceridemia and pancreatitis during childhood or even infancy (chylomicronemia syndrome). Potentially atherogenic roles for LPL have been identified that affect the metabolism and uptake of atherogenic lipoproteins by the liver and the arterial wall and that impact the dyslipidemia of insulin resistance
- #17 After LPL-mediated removal of much of the dietary triglycerides, the chylomicron remnants, which still contain all of the dietary cholesterol, detach from the capillary surface and within minutes are removed from the circulation by the liver (Figure 31–1). First, the remnants are sequestered by the interaction of apoE with heparan sulfate proteoglycans on the surface of hepatocytes and are processed by hepatic lipase (HL), further reducing the remnant triglyceride content. Next, apoE mediates remnant uptake by interacting with the hepatic LDL receptor or the LDL receptor–related protein (LRP) (Lillis et al., 2008). The multifunctional LRP recognizes a variety of ligands, including apoE, and several ligands unrelated to lipid metabolism. In plasma lipid metabolism, the LRP is important because it is the backup receptor responsible for the uptake of apoE-enriched remnants of chylomicrons and VLDL. Cell-surface heparan sulfate proteoglycans facilitate the interaction of apoE-containing remnant lipoproteins with the LRP, which mediates uptake by hepatocytes. Inherited absence of either functional HL (very rare) or functional apoE impedes remnant clearance by the LDL receptor and the LRP, increasing triglyceride- and cholesterol-rich remnant lipoproteins in the plasma (type III hyperlipoproteinemia). During the initial hydrolysis of chylomicron triglycerides by LPL, apoA-I and phospholipids are shed from the surface of chylomicrons and remain in the plasma. This is one mechanism by which nascent (precursor) HDL are generated. Chylomicron remnants are not precursors of LDL, but the dietary cholesterol delivered to the liver by remnants increases plasma LDL levels by reducing LDL receptor-mediated catabolism of LDL by the liver
- #21 VLDL are produced in the liver when triglyceride production is stimulated by an increased flux of free fatty acids or by increased de novo synthesis of fatty acids by the liver. VLDL particles are 40-100 nm in diameter and are large enough to cause plasma turbidity, but unlike chylomicrons, do not float spontaneously to the top of a tube of undisturbed plasma. ApoB-100, apoE, and apoC-I, C-II, and C-III are synthesized constitutively by the liver and incorporated into VLDL (Table 31–2). If triglycerides are not available to form VLDL, the newly synthesized apoB-100 is degraded by hepatocytes. Triglycerides are synthesized in the endoplasmic reticulum, and along with other lipid constituents, are transferred by MTP to the site in the endoplasmic reticulum where newly synthesized apoB-100 is available to form nascent (precursor) VLDL. Small amounts of apoE and the C apoproteins are incorporated into nascent particles within the liver before secretion, but most of these apoproteins are acquired from plasma HDL after the VLDL are secreted by the liver. ApoA-V modulates plasma triglyceride levels, possibly by several mechanisms: inhibition of hepatic VLDL triglyceride production and secretion, promoting LPL-mediated hydrolysis of chylomicrons and VLDL triglycerides, and facilitating hepatic uptake of triglyceride-rich lipoproteins and their remnants (Wong and Ryan, 2007). ApoA-V is produced solely by the liver, and despite its very low plasma concentration (0.1% of the concentration of apoA-I), profoundly affects plasma triglyceride levels in mice and humans. Without MTP, hepatic triglycerides cannot be transferred to apoB-100. As a consequence, patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (VLDL, IDL, or LDL). MTP also plays a key role in the synthesis of chylomicrons in the intestine, and mutations of MTP that result in the inability of triglycerides to be transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorder abetalipoproteinemia. Experimental compounds that interfere with MTP function reduce triglyceride levels but cause hepatic steatosis that has precluded their use in humans. New approaches to MTP inhibition are under study (Hussain and Bakillah, 2008
- #23 Plasma VLDL is then catabolized by LPL in the capillary beds in a process similar to the lipolytic processing of chylomicrons (Figure 31–1). When triglyceride hydrolysis is nearly complete, the VLDL remnants, usually termed IDL, are released from the capillary endothelium and reenter the circulation. ApoB-100 containing small VLDL and IDL (VLDL remnants), which have a t1/2 <30 minutes, have two potential fates. About 40-60% are cleared from the plasma by the liver via interaction with LDL receptors and LRP, which recognize ligands (apoB-100 and apoE) on the remnants. LPL and HL convert the remainder of the IDL to LDL by removal of additional triglycerides. The C apoproteins, apoE, and apoA-V redistribute to HDL. Virtually all LDL particles in the plasma are derived from VLDL. ApoE plays a major role in the metabolism of triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, VLDL, and IDL). About half of the apoE in the plasma of fasting subjects is associated with triglyceride-rich lipoproteins, and the other half is a constituent of HDL. About three-fourths of the apoE in plasma is synthesized by the liver; brain and macrophages synthesize the bulk of the remainder.
- #25 The liver expresses a large complement of LDL receptors and removes 75% of all LDL from the plasma. Consequently, manipulation of hepatic LDL receptor gene expression is a most effective way to modulate plasma LDL-C levels. Thyroxine and estrogen enhance LDL receptor gene expression, which explains their LDL-C–lowering effects. The most effective dietary alteration (decreased consumption of saturated fat and cholesterol) and pharmacological treatment (statins) for hypercholesterolemia act by enhancing hepatic LDL receptor expression. Regulation of LDL receptor expression is part of a complex process by which cells regulate their free cholesterol content. This regulatory process is mediated by transcription factors called sterol regulatory element binding proteins (SREBPs) and SREBP cleavage activating protein (Scap) (Radhakrishnan et al., 2008). Scap is both a sensor of cholesterol content in the endoplasmic reticulum (ER) and an escort of SREBPs from the ER to the Golgi apparatus. In the Golgi apparatus, SREBPs undergo proteolytic cleavage, and a dimer of the amino-terminal domain, transported by importin , translocates to the nucleus, where it activates expression of the LDL receptor gene and of other genes encoding enzymes involved in cholesterol biosynthesis. Increased ER cholesterol content binds Scap, precluding Scap from escorting SREBP to the Golgi apparatus for processing and ultimately from reaching the nucleus
- #26 LDL becomes atherogenic when modified by oxidation (Witztum and Steinberg, 2001), a required step for LDL uptake by the scavenger receptors of macrophages. This process leads to foam-cell formation in arterial lesions. At least two scavenger receptors (SRs) are involved (SR-AI/II and CD36). Knocking out either receptor in transgenic mice retards the uptake of oxidized LDL by macrophages. Expression of the two receptors is regulated differently: SR-AI/II appears to be expressed more in early atherogenesis, and CD36 expression is greater as foam cells form during lesion progression. Despite the large body of evidence implicating oxidation of LDL as a requisite step during atherogenesis, controlled clinical trials have not unequivocally demonstrated the efficacy of antioxidant vitamins in preventing vascular disease
- #27 The metabolism of HDL is complex because of the multiple mechanisms by which HDL particles are modified in the plasma compartment. ApoA-I is the major HDL apoprotein, and its plasma concentration is a more powerful inverse predictor of CHD risk than is the HDL-C level (Mahley et al., 2008). ApoA-I synthesis is required for normal production of HDL. Mutations in the apoA-I gene that cause HDL deficiency are variable in their clinical expression and often are associated with accelerated atherogenesis. Conversely, overexpression of apoA-I in transgenic mice protects against experimentally induced atherogenesis. Mature HDL can be separated by ultracentrifugation into HDL2 (d = 1.063-1.125 g/mL), which are larger, more cholesterol-rich lipoproteins (70-100 Å in diameter), and HDL3 (d = 1.125-1.21 g/mL), which are smaller particles (50-70 Å in diameter). In addition, two major subclasses of mature HDL particles in the plasma can be differentiated by their content of the major HDL apoproteins, apoA-I and apoA-II (Movva and Rader, 2008). Epidemiologic evidence in humans suggests that apoA-II may be atheroprotective (Birjmohun et al., 2007; Movva and Rader, 2008). Lipoprotein particles may be distinguished by their electrophoretic mobities: mature HDL particles have mobility; LDL particles show mobility. The precursor of most of the -migrating plasma HDL is a discoidal particle containing apoA-I and phospholipid, called pre-1 HDL because of its pre-1 electrophoretic mobility. Pre-1 HDL are synthesized by the liver and the intestine, and they also arise when surface phospholipids and apoA-I of chylomicrons and VLDL are lost as the triglycerides of these lipoproteins are hydrolyzed. Discoidal pre-1 HDL can then acquire free unesterified cholesterol from the cell membranes of tissues, such as arterial wall macrophages. Two macrophage membrane transporters, ABCA1 and ABCG1, promote the efflux of cholesterol from macrophages of humans studied in vivo. Prior studies in vitro suggested that another transport protein, class B, type I scavenger receptor (SR-BI) facilitates cholesterol egress from macrophages to HDL, but in vivo studies in humans do not support an important role for SR-BI in this process (Wang et al., 2007). However, SR-BI in the liver facilitates the uptake of cholesteryl esters from HDL without internalizing and degrading the lipoproteins. The membrane transporter ABCA1 facilitates the transfer of free cholesterol from cells to HDL (Attie, 2007). When ABCA1 is defective, the acquisition of cholesterol by HDL is greatly diminished, and HDL levels are markedly reduced because poorly lipidated nascent HDL are metabolized rapidly. Loss-of-function mutations of ABCA1 cause the defect observed in Tangier disease, a genetic disorder characterized by extremely low levels of HDL and cholesterol accumulation in the liver, spleen, tonsils, and neurons of peripheral nerves. Transgenic animals overexpressing ABCA1 in the liver and macrophages have elevated plasma levels of HDL and apoA-I and reduced susceptibility to atherosclerosis (Van Eck et al., 2006).
- #29 The metabolism of HDL is complex because of the multiple mechanisms by which HDL particles are modified in the plasma compartment. ApoA-I is the major HDL apoprotein, and its plasma concentration is a more powerful inverse predictor of CHD risk than is the HDL-C level (Mahley et al., 2008). ApoA-I synthesis is required for normal production of HDL. Mutations in the apoA-I gene that cause HDL deficiency are variable in their clinical expression and often are associated with accelerated atherogenesis. Conversely, overexpression of apoA-I in transgenic mice protects against experimentally induced atherogenesis. Mature HDL can be separated by ultracentrifugation into HDL2 (d = 1.063-1.125 g/mL), which are larger, more cholesterol-rich lipoproteins (70-100 Å in diameter), and HDL3 (d = 1.125-1.21 g/mL), which are smaller particles (50-70 Å in diameter). In addition, two major subclasses of mature HDL particles in the plasma can be differentiated by their content of the major HDL apoproteins, apoA-I and apoA-II (Movva and Rader, 2008). Epidemiologic evidence in humans suggests that apoA-II may be atheroprotective (Birjmohun et al., 2007; Movva and Rader, 2008). Lipoprotein particles may be distinguished by their electrophoretic mobities: mature HDL particles have mobility; LDL particles show mobility. The precursor of most of the -migrating plasma HDL is a discoidal particle containing apoA-I and phospholipid, called pre-1 HDL because of its pre-1 electrophoretic mobility. Pre-1 HDL are synthesized by the liver and the intestine, and they also arise when surface phospholipids and apoA-I of chylomicrons and VLDL are lost as the triglycerides of these lipoproteins are hydrolyzed. Discoidal pre-1 HDL can then acquire free unesterified cholesterol from the cell membranes of tissues, such as arterial wall macrophages. Two macrophage membrane transporters, ABCA1 and ABCG1, promote the efflux of cholesterol from macrophages of humans studied in vivo. Prior studies in vitro suggested that another transport protein, class B, type I scavenger receptor (SR-BI) facilitates cholesterol egress from macrophages to HDL, but in vivo studies in humans do not support an important role for SR-BI in this process (Wang et al., 2007). However, SR-BI in the liver facilitates the uptake of cholesteryl esters from HDL without internalizing and degrading the lipoproteins. The membrane transporter ABCA1 facilitates the transfer of free cholesterol from cells to HDL (Attie, 2007). When ABCA1 is defective, the acquisition of cholesterol by HDL is greatly diminished, and HDL levels are markedly reduced because poorly lipidated nascent HDL are metabolized rapidly. Loss-of-function mutations of ABCA1 cause the defect observed in Tangier disease, a genetic disorder characterized by extremely low levels of HDL and cholesterol accumulation in the liver, spleen, tonsils, and neurons of peripheral nerves. Transgenic animals overexpressing ABCA1 in the liver and macrophages have elevated plasma levels of HDL and apoA-I and reduced susceptibility to atherosclerosis (Van Eck et al., 2006).
- #31 3. Uptake of chemically modified LDL by macrophage scavenger receptors: In addition to the highly specific and regulated receptor -mediated pathway for LDL uptake described above, macrophages possess high levels of scavenger receptor activity. These receptors, known as scavenger receptor class A (SR-A), can bind a broad range of ligands, and mediate the endocytosis of chemically modified LDL in which the lipid components or apo B have been oxidized. Unlike the LDL receptor, the scavenger receptor is not down-regulated in response to increased intracellular cholesterol. Cholesteryl esters accumulate in macrophages and cause their transformation into “foam” cells, which participate in the formation of atherosclerotic plaque
- #37 The Metabolic Syndrome: Introduction The metabolic syndrome (syndrome X, insulin resistance syndrome) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM). The criteria for the metabolic syndrome have evolved since the original definition by the World Health Organization in 1998, reflecting growing clinical evidence and analysis by a variety of consensus conferences and professional organizations. The major features of the metabolic syndrome include central obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, hyperglycemia, and hypertension (Table 242-1). Table 242–1. NCEP:ATPIII 2001 and IDF Criteria for the Metabolic Syndrome NCEP:ATPIII 2001 IDF Criteria for Central Adipositya Three or more of the following: Waist circumference Central obesity: Waist circumference >102 cm (M), >88 cm (F) Men Women Ethnicity Hypertriglyceridemia: Triglycerides 150 mg/dL or specific medication 94 cm 80 cm Europid, Sub-Saharan African, Eastern and Middle Eastern Low HDL cholesterol: <40 mg/dL and <50 mg/dL, respectively, or specific medication 90 cm 80 cm South Asian, Chinese, and ethnic South and Central American Hypertension: Blood pressure 130 mm systolic or 85 mm diastolic or specific medication 85 cm 90 cm Japanese Fasting plasma glucose 100 mg/dL or specific medication or previously diagnosed Type 2 diabetes Two or more of the following: Fasting triglycerides >150 mg/dL or specific medication HDL cholesterol <40 mg/dL and <50 mg/dL for men and women, respectively, or specific medication Blood pressure >130 mm systolic or >85 mm diastolic or previous diagnosis or specific medication Fasting plasma glucose 100 mg/dL or previously diagnosed Type 2 diabetes aIn this analysis, the following thresholds for waist circumference were used: white men, 94 cm; African-American men, 94 cm; Mexican-American men, 90 cm; white women, 80 cm; African-American women, 80 cm; Mexican-American women, 80 cm. For participants whose designation was "other race—including multiracial," thresholds that were once based on Europid cut points (94 cm for men and 80 cm for women) and once based on South Asian cut points (90 cm for men and 80 cm for women) were used. For participants who were considered "other Hispanic," the IDF thresholds for ethnic South and Central Americans were used. Abbreviations: HDL, high-density lipoprotein; IDF, International Diabetes Foundation; NCEP:ATPIII, National Cholesterol Education Program, Adult Treatment Panel III.
- #45 Chylomicrons are assembled in intestinal mucosal cells and carry dietary triacylglycerol, cholesterol, fat-soluble vitamins, and choles teryl esters (plus additional lipids made in these cells) to the peripheral tissues (Figure 18.16). [Note: TAGs account for close to 90% of the lipids in a chylomicron.] 1. Synthesis of apolipoproteins: Apolipoprotein B-48 is unique to chylomicrons. Its synthesis begins on the rough ER; it is glycosylated as it moves through the RER and Golgi. [Note: Apo B-48 is so named because it constitutes the N-terminal, 48% of the protein coded for by the gene for apo B. Apo B-100, which is synthesized by the liver and found in VLDL and LDL, represents the entire protein coded for by the apo B gene. Posttranscriptional editing (see p. 457) of a cytosine to a uracil in intestinal apo B-100 mRNA creates a nonsense codon (see p. 433), allowing translation of only 48% of the mRNA.] 2. Assembly of chylomicrons: The enzymes involved in triacyl glycerol, cholesterol, and phospholipid synthesis are located in the smooth ER. Assembly of the apolipoproteins and lipid into chylomicrons requires microsomal triacylglycerol transfer protein (MTP, see p. 178), which loads apo B-48 with lipid. This occurs before transition from the ER to the Golgi, where the particles are packaged in secretory vesicles. These fuse with the plasma membrane releasing the lipoproteins, which then enter the lymphatic system and, ultimately, the blood. 3. Modification of nascent chylomicron particles: The particle released by the intestinal mucosal cell is called a “nascent” chylomicron because it is functionally incomplete. When it reaches the plasma, the particle is rapidly modified, receiving apolipo protein E (which is recognized by hepatic receptors) and C. The latter includes apo C-II, which is necessary for the activation of lipoprotein lipase , the enzyme that degrades the triacylglycerol contained in the chylomicron (see below). The source of these apolipoproteins is circulating HDL (see Figure 18.16).
- #50 HDL comprise a heterogeneous family of lipoproteins with a complex metabolism that is not yet completely understood. HDL particles are formed in blood by the addition of lipid to apo A-1, an apolipo protein made by the liver and intestine and secreted into blood. Apo A-1 accounts for about 70% of the apoproteins in HDL. HDL perform a number of important functions, including the following: 1. HDL is a reservoir of apolipoproteins: HDL particles serve as a circulating reservoir of apo C-II (the apolipoprotein that is transferred to VLDL and chylomicrons, and is an activator of lipoprotein lipase ), and apo E (the apolipoprotein required for the receptormediated endocytosis of IDLs and chylomicron remnants). 2. HDL uptake of unesterified cholesterol: Nascent HDL are diskshaped particles containing primarily phospholipid (largely phosphatidylcholine) and apolipoproteins A, C, and E. They take up cholesterol from non-hepatic (peripheral) tissues and return it to the liver as cholesteryl esters (Figure 18.23). [Note: HDL particles are excellent acceptors of unesterified cholesterol as a result of their high concentration of phospholipids, which are important solubilizers of cholesterol.] 3. Esterification of cholesterol: When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme lecithin:cholesterol acyltransferase ( LCAT , also known as PCAT , in which “P” stands for phosphatidylcholine). This enzyme is synthesized by the liver. LCAT binds to nascent HDL, and is activated by apo A-I. LCAT transfers the fatty acid from carbon 2 of phosphatidylcholine to cholesterol. This produces a hydrophobic cholesteryl ester, which is sequestered in the core of the HDL, and lyso phosphatidylcholine, which binds to albumin. [Note: Esterification maintains the cholesterol concentration gradient, allowing continued efflux of cholesterol to HDL.] As the discoidal nascent HDL accumulates cholesteryl esters, it first becomes a spherical, relatively cholesteryl ester–poor HDL3 and, eventually, a cholesteryl ester–rich HDL2 particle that carries these esters to the liver. Cholesterol ester transfer protein ( CETP , see p. 231) moves some of the cholesteryl esters from HDL to VLDL in exchange for triacylglycerol, relieving product inhibition of LCAT . Because VLDL are catabolized to LDL, the cholesteryl esters are ultimately taken up by the liver. 4. Reverse cholesterol transport: The selective transfer of cholesterol from peripheral cells to HDL, and from HDL to the liver for bile acid synthesis or disposal via the bile, and to steroidogenic cells for hormone synthesis, is a key component of cholesterol homeostasis. This is, in part, the basis for the inverse relationship seen
- #51 between plasma HDL concentration and atherosclerosis, and for HDL’s designation as the “good” cholesterol carrier. Reverse cholesterol transport involves efflux of cholesterol from peripheral cells to HDL, esterification of cholesterol by LCAT , binding of the cholesteryl ester–rich HDL (HDL2) to liver and steroidogenic cells, the selective transfer of the cholesteryl esters into these cells, and the release of lipid-depleted HDL (HDL3). The efflux of cholesterol from peripheral cells is mediated, at least in part, by the transport protein, ABCA1. [Note: Tangier disease is a very rare deficiency of ABCA1, and is characterized by the virtual absence of HDL particles due to degradation of lipid-poor apo A-1.] The uptake of cholesteryl esters by the liver is mediated by a cell-surface receptor, SR-B1 (scavenger receptor class B type 1) that binds HDL (see p, 234 for SR-A). It is not yet clear as to whether the HDL particle itself is taken up, the cholesteryl esters extracted, and the lipid-poor HDL released back into the blood, or if there is selective uptake of the cholesteryl ester alone. [Note: Hepatic lipase , with its ability to degrade both TAG and phospholipids, also participates in the conversion of HDL2 to HDL3.]