very - low - density lipoprotein ( vldl ) and chylomicrons ( cm ) comprise the triacylglycerol-(tag- ) rich lipoproteins in the circulation the basic structure of vldl is such that the hydrophobic triacylglycerol molecules , together with cholesterol ester , form the particle core and are coated by a relatively hydrophilic monolayer consisting of phospholipids , free - cholesterol , and apolipoproteins     [ 13 ] . apolipoprotein ( apo ) b100 is a 4536 amino acid glycoprotein , synthesised in the liver and the major structural protein of vldl . interestingly , each vldl particle has just one copy of apo - b100 , which means the concentration of apo - b100 represents the number of particles , and this molecule constitutes the basic scaffolding , upon which other compositional components are attached during the assembly process of the lipoprotein . the tag core of the vldl particle is synthesised by liver cells using different endogenous fatty acid sources . these include fatty acids derived from hydrolysis of adipose tissue tag stores ( lipolysis ) , fatty acids derived from peripheral hydrolysis of plasma lipoprotein ( vldl and chylomicron ) tag cleared by the liver , and newly synthesised fatty acids via hepatic de novo lipogenesis . therefore , vldl has been regarded as a transport vehicle responsible for redistribution of endogenous lipids from liver to peripheral tissues . it appears that the major function of hepatic vldl secretion is to buffer plasma  free , the consequence of this conversion is that energy contained within fatty acid is stored and transported in an alternative ( nontoxic ) form , the esterified fatty acid - vldl tag core . this is of particular importance for the heart since lipids are the major cardiac energy substrates . cardiac function is critically dependent on substrate utilisation , and changes in myocardial substrate selection can have a major impact , both positively and negatively , on myocardial contraction . the heart is capable of utilising a wide variety of substrates including carbohydrates , lipids , amino acids , and ketone bodies for its energy requirements , but this utilisation is condition - dependent according to substrate availability and work load . although amino acids and ketone bodies are energetic substrates for heart , the heart 's energy requirement is mainly furnished by provision of circulating carbohydrates and lipids through the coronary vasculature under normal aerobic conditions . the heart can also use its internal stores of energy , that is , glycogen and tag , under certain circumstances , but this supply is quantitatively limited . however , current evidence suggests that most ( ~70% ) of energy for heart is derived from the oxidation of fatty acids under physiological work load conditions     [ 1 , 68 ] . this conclusion has raised another important question . because fatty acids are derived from both plasma albumin - bound nonesterified fatty acids ( nefas ) and plasma tag - rich lipoproteins ( tgrlps ) , that is , vldl and chylomicrons , what therefore is the relative contribution of each lipid source to the cardiac energy requirement ? so far , many studies have been conducted to investigate the utilisation of nefa ( and to a lesser extent , chylomicrons ) by heart . however , unlike these two fa sources , the true physiological role of vldl within cardiac energy metabolism still remains uncertain : very few studies have been reported , and findings from these studies are somewhat discrepant . in this paper , we review these reports on the utilisation of vldl by the myocardium , aiming to outline the possible role of vldl in heart metabolism . since the pioneering studies of bing et al . , it has been fully appreciated that fatty acids are important substrates for myocardial energy requirements . however , it has not been clear what is the contribution of non - esterified fatty acid and esterified fatty acid to myocardial energy production . even four decades later , it was still widely presumed that nefa is the primary source of energy for the heart     [ 8 , 10 ] , despite the fact that the molar concentration of fatty acid in tag - rich lipoproteins may be up to an order of magnitude greater than that of albumin - bound nefa . however , in 1960 , ballard and colleagues suggested that it was actually esterified fatty acids which accounted for most of the total fatty acids extracted by the myocardium . they found that during fasting more than 50% of fatty acids taken up by human hearts were derived from esterified fatty acids ; in fasting dog , this figure was 77% . importantly , this was the first experiment to show that the heart can utilise vldl as a fuel because during fasting most of the esterified fatty acids are transported within the vldl - tag core . unfortunately , since then , although there have been some investigations on lipoprotein utilisation by heart     [ 13 , 14 ] , compared to the multiple studies on cardiac non - esterified fatty acid metabolism , relatively few studies have examined this aspect of myocardial substrate selection . this is partly due to the difficulty in obtaining sufficient quantities of vldl to test in an isolated heart system . in 2000 , bennett et al . reported an extended liver perfusion technique to prepare species - specific radiolabelled vldl .   following this technique , hauton et al . investigated myocardial lipid substrate preference by comparing utilisation of nefa , vldl - tag , and cm - tag in isolated rat  working in other words , like nefa and cm , vldl is capable of supporting the heart energetically . however , some differences did exist : for example , the utilisation of vldl - tag by hearts was less than that of nefa and cm - tag . mechanical performance of hearts perfused with vldl as the sole source of lipid was comparable to those perfused with cm and/or nefa , suggesting either that glucose oxidation is increased in vldl perfused hearts , which has been shown not to be the case by our own work     , or that  efficiency  of vldl - tag utilisation is greater than that of cm - tag or nefa ( same work output for less substrate oxidised ) . if this is true , it could reasonably explain why under some energy stress conditions , such as diabetes      and sepsis , the utilisation and oxidation of vldl are significantly increased . indeed , in our previous work , there was evidence supporting this hypothesis : when the uptake pathway for vldl was blocked , cardiac mechanical performance was severely affected , suggesting an important physiological role for this relatively small amount of lipid substrate assimilated by the heart . using radio - labelled vldl particles from rat liver perfusions in isolated rat  working  heart preparations , we found that under normal physiological conditions , the myocardial uptake and utilisation of vldl was less than that of cm , but mechanical function of the heart was comparable . another significant difference was that only about half the vldl - tag assimilated by the heart was oxidized , whereas the proportion of cm - tag oxidised reached 80% , indicating that the portion of tag - rich lipoprotein - derived lipid channelled towards nonoxidative pathways ( e.g. , incorporation into tissue lipids ) was protected . considering that the heart can utilise carbohydrates , nefa , cm , vldl , amino acids , and so on as its fuel substrates under physiological conditions , vldl probably functions differently to nefa and cm in myocardial energy metabolism . .      found that cm - tag utilisation but not vldl - tag utilisation was suppressed in the presence of nefa . however , tag did not alter nefa utilisation , suggesting that nefa provides a significant contribution to the energy requirements of the working heart , whilst vldl - derived lipid is preferentially required for nonoxidative metabolism . however , there are studies challenging this conclusion . elegant experiments by goldberg 's group utilising labelled tag emulsions   suggested that fatty acid derived from the hydrolysis of tag - rich lipoproteins may be the primary source of fatty acid utilised by the heart , particularly in the fed state . by using a new animal model with overexpression of anchored lipoprotein lipase ( lpl ) on the surface of cardiomyocytes ( hlpl mice ) , pillutla et al .   also found that vldl isolated from fasting blood inhibited the uptake and oxidation of palmitate in the perfusate of both hlpl and wild - type hearts , suggesting that hearts can use tag - derived fatty acids as an alternative fuel , and in some situations , as the primary source of fatty acid . direct measurements of cm - tag utilisation by mouse heart supports the importance of tag - rich lipoproteins in cardiac energy provision     [ 20 , 21 ] . furthermore , tissue - specific inhibition of cardiac tag uptake by selective cardiac lpl knockout reveals both that the heart is a quantitatively important  sink  for plasma tag   and that long - term cardiac function depends on adequate tag provision ( see below ) . therefore , there is now little doubt that vldl plays an important role in myocardial energetics and function , at least by acting as a metabolic substrate . but the difference in this aspect between vldl and other lipid sources , such as cm and nefa , could be of more important significance .   because its utilisation by the heart is relatively low but its efficiency is high , it is possible that vldl serves as an alternative source of fatty acids for hearts under energy - stress conditions ; however , under normal conditions , cm and nefa are the major fatty acid ( oxidative ) sources for the heart whilst vldl might play a regulatory role in myocardial lipid metabolism . in 1943 , hahn reported that following heparin injection , the dog had decreased postprandial lipaemia , indicating that heparin caused the presence of a so - called lipid  clearing factor  in the circulation . this was the first work suggesting the role of lipoprotein lipase ( lpl , e.c.3.1.1.34 ) in lipoprotein metabolism . it is now believed that lpl is the principal enzyme responsible for hydrolysis of tag circulating within lipoproteins , making the fatty acids released available for use by subjacent tissues . there is strong evidence that heart expresses the lpl gene abundantly     [ 25 , 26 ] . indeed , cardiac lpl activity alone ( in the absence of lpl expression in other tissues ) can normalise plasma tag concentration in cardiac rescue lpl knockout mice     . lpl is synthesised by parenchymal heart cells , but requires subsequent transfer to the luminal surface of the endothelial cell , where it is bound to heparan sulphate proteoglycan ( hspg ) , in order to be physiologically active ( functional ) . hydrolysis of tag by endothelium - bound lpl is widely regarded as the initial step for the  bulk  uptake of lipoprotein - tag by peripheral tissues , including the heart     [ 11 , 22 , 2831 ] . indeed , we found a significant decrease in the uptake and utilisation of vldl - tag ( and cm - tag ) by the heart after lpl activity was inhibited , supporting a major role for lpl in mediating myocardial vldl lipid assimilation , a conclusion supported by cheng and hauton who noted a correlation between cardiac lpl activity and tag uptake during metabolic stress . interestingly , however , cardiac mechanical performance was not affected when vldl utilisation was decreased , suggesting that there could be another mechanism for the heart to take up vldl , and this small pool of vldl is effective in maintaining the heart in good working condition even when lpl - mediated hydrolysis is blocked . it should be noted that lpl - mediated hydrolysis of lipoproteins can occur in the plasma following lpl release from the endothelial cell surface by heparin ; hence , hahn found a rapid clearance of blood lipid after injection of heparin . moreover , some lpl probably dissociate from the endothelial cell in association with the lipoprotein particle during lipolysis and continues to lipolyse tag - rich lipoproteins in the bloodstream . but it is still not clear how much lipolysis occurs on the cell surface compared to the plasma , and what the relative contribution of these two sources of lipolysis is to cardiac energy provision . although lpl is also present on the surface of cardiomyocytes , it is generally believed that the luminal surface of the endothelial cell is the site where hydrolysis of the lipoprotein - tag core take place . however , by using a transgenic mouse model with an lpl transgene construct expressed and anchored on the cardiomyocyte surface , yagyu et al .   found that this pool of lpl was responsible for the increased uptake of tag by the heart . furthermore , a new model of cardiomyopathy was created due to the excessive myocardial uptake of tag via lpl action , suggesting that cardiomyocyte cell surface lpl is physiologically functional in terms of mediation of cardiac tag uptake . as reactant and product of the lipolytic process , respectively , tag and free fatty acid have different effects on lpl activity . circulating tag increased lpl activity at the coronary lumen but decreased it on the cardiomyocyte cell surface , suggesting that tag facilitates lpl translocation from cardiomyocyte to the myocardial endothelial lining , and we found that vldl was capable of modulating lpl translocation in isolated hearts     [ 10 , 18 ] . however , anderson et al .      found that free fatty acids selectively decreased heparin - releasable lpl activity in cultured cardiomyocytes , possibly through end - product inhibition of lipolytic processes , and despite an increase in immunodetectable lpl on the cardiomyocyte cell surface . all these studies suggest that lpl is responsible for the uptake of vldl - tag by the heart . however , other factors may be important in vldl assimilation .   in 1967 , enser et al .   used c labelled chyle lipids to perfuse isolated rat hearts . they found that at least part of the co2 production could have been derived from the oxidation of c labelled free fatty acid produced in the perfusion medium via the function of the so - called  clearing - factor lipase  . they also found that the whole lipid particle was being taken up and oxidised by the heart . these results suggested that tag - rich lipoprotein could both be hydrolysed to produce free fatty acid outside the heart and could also be taken up by the heart as a whole particle . to our knowledge , this was the first work to indicate that besides the lpl - mediated hydrolysis there is an alternative mechanism for hearts to assimilate tag - rich lipoproteins . at least two kinds of lipoprotein receptor may be important in the myocardium in this respect : the vldl receptor     [ 3639 ] and the apo - b48 receptor     , both of which have been found in abundance in those tissues active in fatty acid utilisation , including heart , suggesting a potential role in delivery of fatty acid to these tissues for metabolic purposes . the vldl receptor ( vldl - r ) is a 118-kda protein and a member of the expanding mammalian low density lipoprotein receptor ( ldl - r ) gene family with ligand specificity : it binds apo - e but not apo - b . notwithstanding some species differences in tissue distribution of vldl - r , it is reasonable to believe that this receptor is responsible for the delivery of vldl particles into the heart . indeed , since vldl - r cdna was cloned in 1992     , many studies have been performed to identify the function(s ) of this receptor and findings are comparable , which suggests a relationship between myocardial vldl - r expression and vldl uptake . for example , vldl - r protein expression in heart was found to increase progressively with fasting     , suggesting its potential role of delivering vldl - tag to the myocardium since vldl production is increased in fasting . in addition , in hypertrophic hearts , vldl - r mrna decreased     ; the decreased vldl - r expression could be linked to the energy substrate switch from lipid to glucose known to occur in myocardial hypertrophy     [ 45 , 46 ] . also found that in the balb / c fasting mice , vldl - r as well as other molecules involved in cardiac lipid metabolism , including lpl , increased . more recently , zenimaru et al .      found that glucose deprivation from the culture medium significantly induced ampk activation , followed by increased vldl - r expression and hence increased uptake of vldl in rat l6 myoblasts . this is interesting because it suggests that the heart tends to utilise the more  efficient  vldl via regulation of vldl - r expression to deal with the substrate switch from glucose to lipid utilisation which is known to occur in conditions such as fasting , sepsis , and diabetes . however , we used suramin to block lipoprotein receptors on the cardiomyocyte surface   and demonstrated some interesting findings . firstly , vldl - tag fatty acid uptake was not affected during receptor blockade but vldl particle uptake was inhibited ( confirmed by decreased vldl - cholesterol uptake by the heart ) ; secondly , the oxidation rate of vldl - tag significantly decreased and the proportion of tag oxidised also decreased ; thirdly , cardiac mechanical function was significantly impaired following lipoprotein receptor blockade . given that myocardial vldl - tag uptake and utilisation , but not cardiac mechanical function , decreased when lpl was inhibited , these results suggest that , although quantitatively less important than lpl - mediated hydrolysis , vldl receptor - mediated uptake is a functionally critical mechanism for the heart to effectively utilise vldl . furthermore , receptor - mediated tag uptake is preferentially directed towards oxidation rather than esterification , suggesting a correlation between lipid uptake mechanisms and metabolic  channeling  within the cardiomyocyte . unlike the vldl receptor , the apo - b48 receptor is an apo - e- and lpl - independent membrane protein originally found to be responsible for the uptake of tgrlp by reticuloendothelial system ( and hence also termed the tgrlp receptor ) , and believed to deliver lipid and lipid - soluble vitamins to monocyte - macrophages for nutritional purposes under physiological conditions     . clues are that peroxisome proliferator - activated receptor ( ppar)- and ppar activators significantly suppress the expression of apo - b48 receptor mrna in human monocyte - macrophages ; moreover , these activators also inhibit the expression of the apo - b48 receptor protein and ; hence , the receptor - mediated lipid accumulation of tgrlp by monocytes in vitro     [ 50 , 51 ] . because the heart expresses ppar , ppar , and apo - b48 receptor ( albeit the last at relatively low level ) , it is possible that the apo - b48 receptor could also be involved in cardiac lipid metabolism .   clearly , both lpl and lipoprotein receptors ( including the vldl receptor ) are responsible for the uptake of vldl - tag ( as well as chylomicrons remnants     ) by the heart  but several lines of evidence suggest that interactions between the two mechanisms exist .   there are at least three putative mechanisms of interplay between lpl and vldl - r     [ 37 , 38 ] : ( 1 ) as a ligand , lpl can directly bind to the receptor ; ( 2 ) acting as a molecular  bridge  , lpl facilitates the binding of vldl particles to heparan sulphate proteoglycans prior to interaction with the receptor ; ( 3 ) lpl converts vldl particles to smaller remnants ( intermediate density lipoprotein ( idl ) ) , which can subsequently be endocytosed by the receptor ( see ) . however , interactions between vldl - r and lpl could work in a reverse fashion : the vldl receptor acts as an  anchor  to facilitate hydrolysis of tag - rich lipoproteins by lpl     . indeed , vldl - r - deficient mice have reduced lpl activity because the vldl receptor is involved in the translocation of lpl from cardiomyocytes to the endothelial surface , causing hypertriglyceridaemia associated with reduced catabolism of vldl - tag by lpl . further strong support for this mechanism is that receptor - associated protein ( rap ) , a 39-kda protein that inhibits both the ldl receptor - related protein and the vldl receptor , also inhibits lpl activity in mice expressing vldl - r , but rap is less effective in vldl - r knockout animals . the effect of rap on lpl is presumably therefore at least partly via its inhibition of vldl - r , which again supports the concept of the regulation of lpl by vldl - r . although the two mechanisms are responsible for the uptake of   vldl by the heart , under physiological conditions , myocardial utilisation of vldl is relatively low     [ 10 , 18 ] . this suggests that compared to other lipid substrates such as nefa and cm , vldl does not act as a major energy source for hearts in this situation . therefore , what is the true physiological role of vldl ? because it is the ligand for both lpl and vldl - r , vldl itself could be a  bridge connecting the two proteins and act as an important regulator in cardiac energy metabolism ; also , because vldl - tag core is a more  efficient  lipid substrate for the heart     [ 10 , 16 , 18 ] it could be an alternative or  external  energy storage for hearts to utilise in order to adapt to various energy - stress conditions , such as diabetes . in diabetes , downregulated glucose transport and metabolism as the consequence of insulin deficiency ( type 1 ) and resistance ( type 2 ) , result in fatty acid oxidation becoming the almost exclusive energy source for the heart     [ 45 , 56 , 57 ] . little is known about tag metabolism in the diabetic heart , but investigation of myocardial utilisation of vldl in diabetes could provide some clues about the role of this particle in cardiac energy metabolism . to date , the findings relating to cardiac tag metabolism in diabetes are extremely discrepant , making it difficult to discern the true role of vldl , and this may be a reflection of widely varying models of disease severity and length of exposure . both decreased and increased vldl utilisation by the heart have been reported . interestingly , however , the two apparently incompatible findings can each explain two widely accepted features of diabetes : hypertriglyceridaemia and diabetic cardiomyopathy ( a severe cardiovascular complication due to  lipotoxicity  rather than other cardiac risk factors , such as hypertension and coronary atherosclerosis ) . decreased cardiac lpl activity in diabetic rodent hearts has been reported     [ 59 , 60 ] . in 1983 , o'looney et al .   reported decreased vldl metabolism by streptozotocin ( stzs ) induced diabetic hearts , associated with decreased heparin - releasable lpl activity , both effects were completely reversed by the administration of insulin . more recently , cardiac vldl - r protein levels , as well as postheparin lpl activity , were found to decline significantly in stz - induced diabetes     . .   also found that disruption of vldl - r resulted in hypertriglyceridaemia associated with decreased lpl activity in mice . in addition , kobayashi et al .      observed decreased postheparin lpl activity in db / db mice , a type 2 diabetic animal model . these results could explain diabetic hypertriglyceridaemia ; additionally , in support of this mechanism , chen et al . found that hypertriglyceridaemia in stz rats was not primarily due to vldl overproduction in liver but to a peripheral vldl - tag removal defect : since lpl and vldl - r are both down - regulated in diabetes , vldl particles accumulate in the plasma , resulting in hypertriglyceridaemia . however , decreased lpl activity and vldl - r deficiency in diabetes can not explain the increased fatty acid oxidation observed in these hearts , which is another characteristic feature of the diabetic state . in contrast to the findings reported above , meticulous research conducted in rodrigues ' group demonstrated increased cardiac heparin - releasable lpl activity in stz - diabetic   and shr - diabetic rats     , which they hypothesised could increase fatty acid supply to the heart . subsequent studies from the same group confirmed the hypothesis in this model : increased myocardial vldl metabolism associated with elevated heparin - releasable lpl activity in stz - induced moderately diabetic rat hearts was reported     . the authors believed that the rapid removal of vldl - tag by diabetic heart could be one mechanism for the increased provision of fatty acid for energy production , to compensate for the diminished contribution of glucose as an energy source . furthermore , this mechanism could be responsible for the development of diabetic cardiomyopathy due to excess delivery of potentially toxic fatty acid to the heart (  lipotoxicity  ) . intracellular lipids accumulate and can , either by themselves or via production of second messengers such as ceramides , provoke cell death     [ 25 , 65 ] . we found that cardiac heparin - releasable lpl activity increased in both type 1      and type 2 diabetic rats , and vldl - tag oxidation increased significantly in diabetic hearts . in addition , when hearts from both control and diabetic rats were perfused with vldl particles prepared from stz - treated animals , heparin - releasable lpl activity increased , suggesting that diabetic vldl particles may stimulate lpl activity , and indicating a possible regulatory role for vldl . consistent with this , we have also found significant intracellular tag accumulation , derived from exogenous vldl , in both types of diabetes regardless of unimpaired cardiac function at an early stage of the disease     [ 16 , 66 ] . further evidence of a role for vldl as a metabolic signal and cellular regulator has recently been provided by the demonstration that vldl modulates myocardial serca-2 expression and calcium handling , an effect potentiated by hypoxia . one explanation for the variable and condition - dependent nature of vldl action and metabolism may be the complex nature ( and potentially key importance ) of the composition of the vldl particle itself . the apoprotein components maintain the structure of the particles but also have regulatory and signalling functions     ; lipid constituents include tag , phospholipids ( pl ) , cholesterol , cholesterol ester , and free fatty acids , with potentially complex surface interactions with target routes . furthermore , dynamic alterations in the composition of vldl particles occur physiologically as well as pathologically , and this can profoundly affect their efficacy as a target and substrate for both lpl and vldl - r . upon its entry into the bloodstream , vldl acquires apo - c and apo - e by transfer from circulating plasma high - density lipoproteins ( hdl ) . subsequently , the tag core of vldl is hydrolysed by lipoprotein lipase ( lpl ) , resulting in free fatty acid release and formation of smaller remnant particles , that is , intermediate - density lipoprotein ( idl ) , and ultimately low - density lipoprotein ( ldl ) which are enriched in cholesterol . any compositional alteration is of great potential significance regarding metabolism of the lipoprotein particle ( and its remnant ) under pathophysiological conditions . for example , apo - e is an important ligand of vldl - r     [ 36 , 39 ] and can anchor apo - e - rich lipoproteins to the hspg site of the cells . apo - cii is an activator of lpl , whereas apo - ciii inhibits the activity of the enzyme     [ 30 , 36 , 39 ] . several studies have analysed the composition of vldl particles in diabetes     [ 70 , 71 ] . again , however , the results are discrepant . increased     , unchanged , and decreased     [ 16 , 74 ] tag contents in diabetic vldl however , the particle is complex and subtle differences in lipid or apoprotein makeup may have a major impact on subsequent particle efficacy and hence action , and this may in part account for the variable findings . thus , sambandam et al .      found increased myocardial vldl metabolism in type 1 diabetes but also reported that there was no apparent difference in apolipoprotein composition in vldl particles obtained from control and diabetic rats ; the authors considered that vldl prepared from diabetic rats is a normal substrate for lpl . this is in contrast to our own findings      ( as well as o'looney 's earlier work ) although both of these studies also demonstrated increased vldl metabolism in stz - induced diabetes . firstly , we found that the tag  :  pl ratio of vldl particles from diabetic rats was significantly lower compared to control vldl , suggesting that vldl particles in type 1 diabetes are smaller ( since tag  :  pl ratio approximates to core - to - surface ratio and , thus , lipoprotein particle size ) . this is probably a mechanism for vldl particles to adapt to diabetic conditions since increased apo - e content facilitates the interaction between vldl and vldl - r , and hence also between vldl and lpl . by contrast , ishibashi et al .   reported no change in vldl lipid content but they found that apo - ciii / cii ratio increased in diabetes , suggesting a factor contributing to hypertriglyceridaemia since apo - ciii is an inhibitor of lpl . hence , research to date suggests that vldl is indeed a key factor in the pathogenesis of hypertriglyceridaemia and cardiac dysfunction in diabetes , although its precise role is yet to be fully elucidated . meanwhile , evidence remains conflicting ; for example , in human type 1 diabetic patients vldl metabolism has been reported as normal     . furthermore , sambandam et al .      challenged others ' works by demonstrating that elevated tag levels found in stz - diabetic rats was abolished after 16-hour fasting , suggesting that increased chylomicron - tag may contribute to the diabetic hypertriglyceridaemia : like vldl , chylomicrons are abnormal in composition in diabetes     [ 70 , 76 ] and their normally rapid peripheral tissue clearance may therefore also be delayed in this state . such a mechanism would reconcile the coexistence of hypertriglyceridaemia ( cm ) and increased myocardial tag - fa metabolism   ( vldl ) mediated through lpl and vldl - r uptake mechanisms . interestingly , therefore , changes in myocardial vldl utilisation in diabetes can explain the two key features of this metabolic disorder : hypertriglyceridaemia and diabetic cardiomyopathy . by using vldl particles prepared from perfused livers from control and diabetic rats , studies to investigate myocardial vldl utilisation under normal conditions and in various metabolic disease states have been conducted in our lab     [ 16 , 18 , 66 ] . from these studies it has emerged that one possible role of vldl is to act as an exogenous ( extratissue ) energy storage or buffer for the heart .   unlike endogenous myocardial energy storage , that is the intramyocellular pool of tag and glycogen , furthermore , since it is delivered by the blood , it will be accompanied by oxygen , absolutely required for oxidation of tag - derived fatty acid . therefore , the heart mobilises this pool of tag to adapt itself to specific energetic - stress conditions , for example , diabetes and sepsis . conversely , the concept of plasma vldl as a cardiac tag buffer is supported by the observation of lipoprotein secreting capacity by the heart     , permitting two - way interchange of tag / lipoprotein between cardiomyocyte and plasma . such a mechanism would provide the heart with a mechanism to prevent lipid overload and hence lipotoxicity . the key evidence for this is that under physiological conditions only about half of vldl - tag assimilated was oxidised in the cardiomyocyte , and the oxidation rate of vldl - tag was markedly lower than that of cm - tag     [ 10 , 18 ] and nefa     . this suggests that the primary purpose of vldl delivery to the heart may not be for oxidation to produce atp ( although the heart did work well whilst oxidising some of the vldl - tag assimilated     [ 10 , 18 ] ) under these physiological conditions . by contrast , more than 80% of vldl - tag assimilated was oxidised in type 1      and type 2   diabetes , and the oxidation rate was also significantly higher than that under physiological workload . furthermore , we have demonstrated that cardiac vldl metabolism and functional efficacy is significantly increased in sepsis / endotoxinaemia ; vldl is a better cardiac substrate in endotoxinaemia , and this is a function of some change in the composition of the  endotoxic  vldl particle rather than the heart itself , since the effect depends on the endotoxic state of the vldl and not on the endotoxic state of the myocardium . this finding was supported by the demonstration of altered composition of the vldl particle secreted by the endotoxic liver     [ 17 , 78 , 79 ] . the primary importance of the vldl particle per se in determining its function and fate is emphasised by the recent observation that cardiac vldl - r is downregulated in sepsis / endotoxinaemia hence , alterations in vldl composition are essential determinants in its utilisation , irrespective of specific uptake route ( indeed  endotoxic  vldl secreted during sepsis has been suggested as a vital component of the host immune response     [ 81 , 82 ] ) . again , this argues in favour of a vital role for vldl in energy provision in metabolic stress states , a notion supported by the observation of increased hepatic vldl synthesis and secretion in both sepsis     [ 8386 ] and diabetes     [ 70 , 8789 ] . if vldl does provide an energy reserve for the heart , it is understandable that myocardial vldl - r expression is increased during the physiological conditions of development      and fasting     [ 43 , 47 ] : the heart uses this energy storage to adapt itself more efficiently to changing circumstances when undergoing switching of energy substrates . these findings indicate that vldl is mobilised under specified pathophysiological conditions as a major myocardial energy source to provide atp for maintenance of cardiac function . the role of vldl , a tag - rich lipoprotein , in myocardial energy metabolism has yet to be fully elucidated . unlike nefa and cm , however , the heart utilises more vldl for the production of atp in diabetes and sepsis / endotoxinaemia . also , under other conditions such as fasting and development , when energy substrate switching occurs , vldl appears to be an easily accessed energy source for the heart . two possible roles of vldl in terms of cardiac energy metabolism have been suggested : a  metabolic regulator  particularly for lpl activity , and  exogenous energy storage  for hearts .
the heart is a major consumer of energy and is able to utilise a wide range of substrates including lipids . 
 nonesterified fatty acids ( nefa ) were thought to be a favoured carbon source , but their quantitative contribution is limited because of their relative histotoxicity . circulating triacylglycerols ( tags ) in the form of chylomicrons ( cms ) and very - low - density lipoprotein ( vldl ) are an alternative source of fatty acids and 
 are now believed to be important in cardiac metabolism . 
 however , few studies on cardiac utilisation of vldl have been performed and the role of vldl in cardiac energy metabolism remains unclear . 
 hearts utilise vldl to generate atp , but the oxidation rate of vldl - tag is relatively low under physiological conditions ; however , in certain pathological states switching of energy substrates occurs and vldl may become a major energy source for hearts . 
 we review research regarding myocardial utilisation of vldl and suggest possible roles of vldl in cardiac energy metabolism : metabolic regulator and extracardiac energy storage for hearts .