Transport and Metabolism - families (our mentors and colleagues) who make working in the ﬁ eld

Lipid is transported out of the intestine and in plasma in the form of lipoprotein particles. A common feature of lipoprotein particles is their structure. The core of the spherical particle is composed primarily of apolar compo-nents: triacylglycerol and cholesteryl ester. The surface of the particle is composed of the more polar constituents: a

Reproduced with permission from Ginsberg (1994). Copyright Elsevier.

TABLE 9.2 Characteristics of lipoproteins Lipoprotein Density

(g/dL)

Molecular mass (daltons)

Diameter (nm)

Lipid (%) ^a

Triacylglyerol Cholesterol Phospholipid

Chylomicron 0.95 1400 × 10⁶ 75 –1200 80 –95 2 –7 3 –9 VLDL 0.95 –1.006 10 –80× 10⁶ 30 –80 55 –80 5 –15 10 –20 IDL 1.006 –1.019 5 –10× 10⁶ 25 –35 20 –50 20 –40 15 –25 LDL 1.019 –1.063 2.3 × 10⁶ 18 –25 5 –15 40 –50 20 –25 HDL 1.063 –1.21 1.7 –3.6× 10⁵ 5 –12 5 –10 15 –25 20 –30 a Percentage composition of lipids; apolipoproteins make up the rest.

VLDL, very -low-density lipoprotein; IDL, intermediate -density lipoprotein; LDL, low -density lipoprotein;

HDL, high -density lipoprotein.

Lipoprotein Particles

Very -low -density ( VLDL) and Intermediate -density (IDL) Lipoproteins

VLDL are hepatically derived particles that mediate the transport of fat from the liver to peripheral tissue (Frost and Havel, 1998 ; Karpe, 1999 ). The triacylglycerol in VLDL is synthesized from fatty acids derived from de novo lipogenesis (using monosaccharides as substrate), cytoplas-mic triacylglycerol, lipoproteins taken up directly by the liver, and exogenous free fatty acids. The major apolipo-protein in VLDL is apo B - 100 (Tessari et al. , 2009 ). Apo B - 100 is synthesized on the rough endoplasmic reticulum and transferred to the Golgi apparatus where, with the involvement of MTP, it is incorporated into the nascent VLDL particle. Inadequate triacylglycerol or the absence of MTP results in internal degradation of apo B - 100 (Olofsson et al. , 2007 ). This degradation is facilitated by the association of nascent apo B with a cytosolic chaperone protein, heat shock protein 70 (Ginsberg, 1997 ). In plasma, VLDL also contains apo E and apo C, which are either present at the time of secretion or acquired once in the circulation (Frost and Havel, 1998 ; Karpe, 1999 ).

The lipid components of VLDL particles are similar to those of chylomicrons; however, the relative proportion of triacylglycerol is less (Table 9.2 ). This results in smaller, denser particles. Once in circulation, the initial stages of VLDL metabolism are similar to that of chylomicron metabolism. Lipoprotein lipase hydrolyzes the core triacyl-glycerol (Choi et al. , 2002 ; Cilingiroglu and Ballantyne, 2004 ). The resulting fatty acids are taken up by cells locally and are oxidized for energy, used for the synthesis of struc-tural components (phospholipid) or bioactive compounds (leukotrienes, thromboxanes), or stored (triacylglycerol).

Triacylglycerol - depleted particles, VLDL remnants, can either be taken up directly by receptor - mediated mecha-nisms in the liver or remain in circulation and be pro-gressively depleted of triacylglycerol. The delipidation of VLDL results in the progressive shift in the composition of the lipoprotein particle from one deﬁ ned as VLDL to IDL and eventually LDL (Choi et al. , 2002 ; Cilingiroglu and Ballantyne, 2004 ). This process is facilitated not only by lipoprotein lipase, but also by hepatic lipase (Choi et al. , 2002 ; Zambon et al. , 2003 ; Cilingiroglu and Ballantyne, 2004 ). This second lipase has the capacity to hydrolyze both triacylglycerol and phospholipid, and is localized to the liver. The progressive depletion of triacyl-glycerol from the lipoprotein particle results in a marked increase in the relative proportion of cholesterol. In circu-apolipoproteins are added to the surface of chylomicron

particles include apo A - I, apo A - IV, apo A - II, apo C, and apo E (Brown, 2007 ). It has been suggested that the release of apo A - IV is stimulated by dietary fat and has a role in the regulation of upper gut function and satiety (Tso and Liu, 2004 ). It has further been suggested that apo A - IV may be involved in the long - term regulation of food intake and that chronic ingestion of a high - fat diet blunts the intestinal apo A - IV response to dietary fat and hence pre-disposes to obesity (Tso and Liu, 2004 ).

Chylomicrons are assembled from apo B - 48 and triacyl-glycerol accumulated in the smooth endoplasmic reticu-lum. Microsomal triacylglycerol transfer protein (MTP) is responsible for transporting and inserting the triacyl-glycerol into the nascent chylomicron core as the particle is then transferred into the lumen of the endoplasmic reticulum (White et al. , 1998 ). Some data suggest that small apo B - 48 - containing particles fuse with large, inde-pendently formed triacylglycerol apo B - 48 free particles prior to secretion (Mu and Hoy, 2004 ; Kindel et al. , 2010 ).

Carbohydrate is added to the nascent chylomicron particle just before release from the Golgi apparatus by exocytosis from the cell.

Chylomicrons are released from enterocytes into the lymph before being channeled from the thoracic duct to the subclavian vein. Some of the apolipoproteins associ-ated with chylomicron particles are acquired by transfer after the lipoprotein is released into the bloodstream.

Once in circulation, the triacylglycerol component of chy-lomicron particles is hydrolyzed by lipoprotein lipase.

During this process, apolipoproteins are transferred to other lipoprotein particles. Lipoprotein lipase is synthe-sized in adipose tissue, heart, and skeletal muscle, and migrates to the capillaries where it functions to hydrolyze triglyceride (Merkel et al. , 2002 ; Stein and Stein, 2003 ).

Apo C - II is a critical cofactor for the reaction whereas apo C - I and apo C - III inhibit the reaction (Shachter, 2001 ; Merkel et al. , 2002 ; Saito et al. , 2004 ). The hydrolysis of chylomicron triacylglycerol in the circulation accounts for the delivery of fatty acids from the gastrointestinal system to peripheral tissue for oxidation, metabolism, and storage.

Chylomicron particles depleted of the triacylglycerol com-ponent are taken up by the liver via either the LDL recep-tor or LDL - receprecep-tor - like protein receprecep-tor (Cooper, 1997 ; Havel, 2000 ). The components of chylomicron particles are either used by the liver directly or are incorporated into newly synthesized hepatically derived lipoprotein particles.

highly heritable and affected by the apo(a) gene (LPA) located on chromosome 6q26 - 27. Apo(a) proteins com-prise a family of proteins differing in size. The size of apo(a) is determined by the number of kringle IV repeats incorporated into the protein as a function of the LPA gene size polymorphism [KIV - 2 VNTR]. Although the precise function of Lp(a) remains to be established, high blood Lp(a) concentrations are associated with increased coronary heart disease and stroke risk (Tziomalos et al. , 2009 ; Spence, 2010 ).

High -density Lipoprotein ( HDL)

HDL particles are derived from the liver and intestine. In addition, during delipidation of chylomicrons in the periphery, excess phospholipid and apolipoproteins from the surface of these particles serve as a source of HDL (Merkel et al. , 2002 ). The primary role of HDL particles is to participate in “ reverse cholesterol transport ” by shutt-ling cholesterol from the peripheral tissues to the liver for excretion, metabolism, or storage (Meagher, 2004 ; Morgan et al. , 2004 ). An integral part of this process is scavenger receptor (SR) - B1. This hepatic HDL receptor selectively takes up the cholesteryl ester component of HDL, thus enabling HDL to continually pick up additional choles-terol from peripheral tissue and shuttle it to the liver (Tall, 1998 ; Marcil et al. , 2004 ).

HDL is a heterogeneous group of particles that differ in both the apolipoprotein composition and size. All HDL particles contain apo A - I. Additional apolipoproteins (apo) associated with HDL can include apo A - II, A - IV, and Cs (Brown, 2007 ). HDL particles appear to protect other lipoproteins from oxidative modiﬁ cation. This activity appears to be related to the presence of apo A - I, paraoxo-nase, and platelet - activating factor acetylhydrolase (Ji et al. , 1999 ; Navab et al. , 2004, 2007 ). Plasma HDL levels are inversely related to triglyceride and risk of developing cardiovascular disease (Taskinen, 2003 ; Szapary and Rader, 2004 ).

Tangier disease is an autosomal recessive disorder characterized by the virtual absence of HDL cholesterol.

HDL - mediated cholesterol efﬂ ux, and intracellular lipid trafﬁ cking and turnover, are abnormal in ﬁ broblasts from Tangier patients. The genetic defect encoding for a member of the ATP - binding cassette transporter family has been identiﬁ ed in these individuals (Burris et al. , 2002 ; Oram, 2002 ; Kolovou et al. , 2006 ). The ABC transporter is integral to the process of reverse cholesterol transport.

Individuals with a mutation in the ABC transporter have lation, as VLDL is depleted of triacylglycerol, all

apolipo-proteins with the exception of apo B - 100 are transferred to other lipoprotein particles. The ultimate product is LDL, a cholesterol - rich particle containing only a single copy of apo B - 100.

Low -density Lipoprotein

LDL particles can be taken up by an apolipoprotein -mediated (LDL receptor family) or scavenger receptor (Van Berkel et al. , 2000 ; Linton and Fazio, 2001 ). Several LDL receptor family members exist including the LDL receptor itself, LDL receptor - related protein (LRP), apo E receptor 2 protein, multiple epidermal growth factor containing protein 7, VLDL receptor, LRP1B, megalin, LRP 5, and LRP 6 (May et al. , 2007 ; Lillis et al. , 2008 ; Goldstein and Brown, 2009 ). LDL receptors predominate in tissues such as liver, smooth muscle cells, ﬁ broblasts, central nervous system neurons and astrocytes, epithelial cells of the gastrointestinal tract, testis Leydig cells, ovarian granulosa cells, and kidney dendritic interstitial cells (Moestrup et al. , 1992 ). Whereas the LDL receptor medi-ates the uptake of apo B - 100 or apo E - containing lipopro-teins, other members of the LDL receptor family recognize multiple apolipoproteins, proteases, and protease/inhibitor complexes, and additional signaling molecules as well as playing other diverse biological roles (Bajari et al. , 2005 ).

Once LDL particles are taken up by the cell, they disas-sociate from the receptor which in turn allows the receptor to be recycled. The LDL particle then fuses with a lyso-some and is subsequently degraded. This step is critical for whole - body cholesterol homoeostasis because the choles-terol taken up from circulation and released from the lyso-some has three distinct effects as discussed earlier in the “ Cholesterol and cholesteryl ester ” section. Alternatively, LDL can be taken up by a scavenger receptor on macro-phages in various tissues. Scavenger receptors predominate in macrophages. This system predominates after LDL par-ticles are modiﬁ ed or oxidized as they circulate in plasma (Van Berkel et al. , 2000 ; Linton and Fazio, 2001 ). Whereas the LDL receptor - mediated uptake is rate limited by the ability of unesteriﬁ ed cholesterol to inhibit the synthesis of new receptors, scavenger receptor uptake is proportional to circulating LDL cholesterol concentrations.

Lipoprotein(a) ( Lp[a])

Lipoprotein(a) (Lp[a]) contains an LDL - like particle and a single copy of apo(a), covalently bounded to apoB on the LDL - like particle. Blood Lp(a) concentrations are

try. The health effects of such oils need to be more pre-cisely deﬁ ned.

very low levels of HDL cholesterol and develop premature atherosclerosis.

In addition to delipidation, lipoproteins are altered while in circulation (Borggreve et al. , 2003 ; Miller et al. , 2003 ; Wirtz, 2006 ; Masson et al. , 2009 ). This includes both exchange and modiﬁ cation of lipoprotein constitu-ents. LCAT esteriﬁ es free cholesterol on the surface of HDL particles. Apo A I serves as a co factor and HDL associated phosphotidylcholine as the source of fatty acid (Miller et al. , 2003 ; Masson et al. , 2009 ). The formation of cholesteryl ester and its subsequent migration to the core of the HDL particle creates an environment receptive to the addition of more free cholesterol from peripheral tissue and ensures that the cholesterol already on the HDL particle does not transfer back to peripheral tissue.

Cholesterol ester transfer protein (CETP) facilitates the exchange of cholesteryl ester from HDL to VLDL or chylomicrons for triacylglycerol (Borggreve et al. , 2003 ; Masson et al. , 2009 ). Phospholipid transfer protein activ-ity results in HDL remodeling through the exchange of phospholipid (Wirtz, 2006 ). These processes enhance reverse cholesterol transport.

Future Directions

Several areas of lipid nutrition exist at the forefront of research. First, lipid cellular regulators have been identiﬁ ed recently that affect processes including fat synthesis and breakdown. In particular, a group of ethanolamides has been identiﬁ ed as being derived through a series of enzy-matic steps from dietary fatty acids in the intestinal cells.

Oleoylethanolamide, derived from oleic acid, appears to suppress fat synthesis as well as perhaps to affect appetite (Capasso and Izzo, 2008 ). Another future area of discovery involves transesteriﬁ ed fats. Repositioning the three fatty acids conﬁ gured across a glycerol molecule can profoundly alter the manner by which that triacylglycerol is absorbed and metabolized (Berry, 2009 ). Further research is required to fully deﬁ ne how transesteriﬁ ed triacylglycerol impacts on processes of lipid digestion and utilization.

Another area of current research focus involves the genetic modiﬁ cation of plants to produce vegetable oils with non - traditional fatty acid proﬁ les. For example, plant - based oils enriched in stearidonic or docosahexae-noic acid through genetic enhancement are now available for dietary consumption (Damude and Kinney, 2007 ).

Similarly, fats enriched in oleic acid which function well as substitutes for trans fats are available to the food

indus-Suggestions for Further Reading

Betters, J.L. and Yu , L. ( 2010) NPC1L1 and cholesterol transport. FEBS Lett 584, 2740–2747.

Caesar , R., Fåk, F. , and Bäckhed, F. ( 2010) Effects of gut microbiota on obesity and atherosclerosis via modulation of inﬂ ammation and lipid metabolism . J Intern Med 268, 320–328.

Rothblat, G.H. and Phillips, M.C. ( 2010) High-density lipoprotein heterogeneity and function in reverse cholesterol transport . Curr Opin Lipidol 21, 229–238.

Van der Velde , A.E., Brufau, G., and Groen, A.K. ( 2010) Transintestinal cholesterol efﬂ ux . Curr Opin Lipidol 21, 167–171.

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在文檔中 families (our mentors and colleagues) who make working in the ﬁ eld of nutritional sciences exciting, (頁 147-154)