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Home , Carbohydrate metabolism, Fatty acid metabolism, Fatty acid synthesis, Glycolysis

Int J Clin Exp Med 2018;11(1):59-68 www.ijcem.com /ISSN:1940-5901/IJCEM0056886

Review Article and β-oxidation, which one is the culprit of ischemic ?

Qing Gao1*, Hao Deng2*, Huhu Li1*, Chun Sun1, Yingxin Sun1, Bing Wei1, Maojuan Guo1, Xijuan Jiang1

1School of Integrative Medicine, 2First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. *Equal contributors Received May 5, 2017; Accepted November 14, 2017; Epub January 15, 2018; Published January 30, 2018

Abstract: Thrombolysis therapy and percutaneous coronary intervention are common methods in the treatment of acute myocardial infarction. These methods can recover the cardiac function in most cases. But in almost one-third circumstances, cardiac dysfunction and structural damage aggravated, which is known as ischemia-reperfusion injury. Normally, most ATP in cardiomyocytes was produced from fatty acid β-oxidation. However, both fatty acid β-oxidation and glycolysis accelerated due to AMPK activation during ischemic. Glycolysis uncoupled from oxidation results in intermediate metabolite accumulation, such as lactate, proton, succinate and NADH. During reperfusion, the recovering rate of fatty acid β-oxidation even exceed the rate under physiological condition due to the sudden influx of high concentration of . High rate of fatty acid β-oxidation inhibits glycose oxidation and results in proton and Ca2+ overload, especially huge amount of ROS production, which leads to mitochondria damage and death. Clearly, energy disorder result from the sudden change of oxygen supply during ischemic and reperfusion is the main cause of ischemic reperfusion injury. However, glycolysis and fatty acid β-oxidation, which one is the real culprit in ischemic reperfusion injury is controversial. In this review, we will discuss the process of metabolism and fatty acid β-oxidation thoroughly, as well as the energy sensor AMPK signaling, in order to clarify how to modulate energy metabolism to reduce injury during ischemic and reperfusion.

Keywords: Glycolysis, fatty acid β-oxidation, intermediate metabolite, ischemic reperfusion injury

Introduction FFA in the plasma and the intracellular level of malonyl-CoA can regulate the rate of fatty Although cardiomyocytes were supplied by mul- acid β-oxidation [5, 6]. Malonyl-CoA is synthe- tiple energy sources, fatty acid and glucose are sized from cytosolic acetyl-CoA via acetyl-CoA the main ones. Under physiological condition, carboxylase (ACC), while it is degraded thro- most of its energy was produced from fatty acid ugh malonyl-CoA decarboxylase (MCD) [7, 8]. β-oxidation (FAO) (All abbreviations are listed in Malonyl-CoA regulates fatty acid β-oxidation by Table 1), due to its high efficiency in ATP pro- inhibiting the activity of CPT-I, which is the rate duction. Free fatty acids (FFA) in cardiomyo- limiting of mitochondrial fatty acid cytes generate fatty acyl-CoA following este- uptake, thereby it controls the rate of fatty acids rification reaction, the process of which is cata- entering into the mitochondria for subsequent lyzed by a family of fatty acyl-CoA synthase oxidation [9, 10]. (FACS) [1]. The mitochondrial uptake of fatty acyl-CoA into its matrix is mediated by Since the well-known fact that fatty acid are palmitoyl- I and II (CPT-I, normally the predominant fuel for cardiac ener- II), which are localized to the mitochondrial gy production, aerobic glucose metabolism has outer membrane and inner membrane respec- been neglected in heart. Actually, it is respon- tively [2]. Once enter the mitochondrial matrix, sible for 10%-40% of ATP production in cardio- fatty acyl-CoA are catalyzed via the process of myocytes [11]. Glucose transportation into car- fatty acid β-oxidation, eventually they were dis- diomyocytes was regulated by glucose trans- membered to acyl-CoA that were metabolized porter family members such as GLUT 1 in TCA cycle [3, 4]. Both the level of circulating and 4, which are predominantly expressed at Glycolysis and fatty acid β-oxidation disorder in IR

Table 1. List of abbreviations Actually, the heart is an organ that can Full name Abbreviate exert maximum function when it apply different energy sources simultane- Fatty acid β-oxidation FAO ously [11]. In aerobic condition, high Free fatty acids FFA rate of fatty acid β-oxidation can inhibit Acyl-CoA synthase FACS glucose oxidation in cardiomyocytes. Carnitine palmitoyl-transferase I and II CPT-I, II This phenomenon is based on the Malonyl-CoA decarboxylase MCD Randle cycle [20], in which fatty acid- Acetyl-CoA carboxylase ACC derived acetyl CoA can decrease the Pyruvate decarboxylase PDC production of glucose-derived acetyl 6-phosphofructo-1- PFK-1 CoA via inhibition of the pyruvate dehy- drogenase complex. On the other side, Reactive oxygen species ROS under anoxic condition, energy-provi- Ischemic reperfusion IR sion way switch into the more efficient ETC way, glycolysis but brings harmful Activated AMPK metabolites. Any alterations in energy adenine dinucleotide NDAH metabolism can contribute to develop- Reverse electron transport RET ment of heart diseases, including IR Coenzyme Q CoQ injury. Optimizing energy metabolism binding module CBM in the heart is a feasible and important approach to treat IRI. Under this con- Cystathionine-b-synthase CBS cept, we recapitulate myocardial ener- kinase B1 LKB1 gy metabolism and its relevance to IR injury. the surface of adult cardiomyocytes [12]. Alterations of glycolysis and fatty acid Intracellular glucose is rapidly phosphorylated β-oxidation and becomes a for the glycolytic pathway, synthesis, and syn- Ischemic thesis [13, 14]. Once entering the glycolytic pathway, the process will be examined by key During ischemia, ATP production from electron enzymes such as , 6-phosphofruc- transport chain (ETC) is almost terminated to-1-kinase (PFK-1) and [15]. without oxygen. It results in AMP accumulated, Pyruvate enters the mitochondria via a mono- which activate Adenosine Monophosphate Ac- carboxylate carrier, and becomes a cross point tivated Protein Kinase (AMPK) signaling (Figure for several metabolic pathways. For example, it 1) [21]. Activated AMPK can accelerate both can produce lactate glycolysis; it can convert to glucose and fatty acid β-oxidation through relo- acetyl-CoA by pyruvate decarboxylase (PDC), cating GLUT4 and /CD36 to sarcolemma as and transform into oxaloacetate [16]. well as phosphorylating PFK-1 and inhibiting ACC [22]. Subsequently, malonyl-CoA decre- Although ischemic treatment such as coronary ase thus relieves the inhibition of CPT-1 [23]. bypass surgery, thrombolysis, and percutane- However, Krebs cycle cannot disposal the huge ous coronary intervention achieved significant amount of Acetyl-CoA from glucose and fatty accomplishment, ischemic reperfusion (IR) in- acid oxidation with blocked ETC [24]. As a con- jury is still to be solved [17]. Reactive oxygen sequence, Acetyl-CoA produced from fatty acid species (ROS) and Ca2+ overload are the main β-oxidation will inhibit PDC, i.e. Randle cycle as culprits as supported by many researchers previously described, and results in glycolysis [18]. But the resources of ROS and Ca2+ are still that uncoupled with ATP production [25]. In under debates. During ischemic and reperfu- addition, fatty acid accumulate in cytoplasma sion process, oxygen supply in cardiomyocytes under both prandial state and catecholamine changed suddenly, which cause energy metab- discharge. Catecholamine discharge was up- olism disorder and further damage [19]. The regulated in the ischemic stress, together with heart has a very high energy demand, and of plasma levels [26]. Catech- course, oxygen demand. Energy metabolism olamines stimulate adipose , pathway changes with oxygen concentration. decrease pancreatic release, and des-

60 Int J Clin Exp Med 2018;11(1):59-68 Glycolysis and fatty acid β-oxidation disorder in IR

reuptake of Ca2+ into the sar- coplasmic reticulum, respec- tively, leads to intracellular Ca2+ overload, which in turn increases the production of free radicals. This also chang- es the affinity of different pro- teins, such as enzymes and troponin C, to Ca2+ [35], modi- fies tertiary protein structures, inhibits enzymes and disrupts the function of sarcoplasmic pumps and carriers [36-38]. Low dose of Na+/Ca2+ exch- ange inhibitor protects isch- emic reperfusion injury in rat hearts [39]. In general, glycol- ysis generates ATP for cardio- Figure 1. Alterations of glucose and fatty acid β-oxidation metabolism dur- ing ischemic. AMP accumulation during ischemic leads to AMPK activation, myocytes utilization, but also which accelerate both glucose and fatty acid β-oxidation. High rate of fatty results in intracellular acido- acid β-oxidation results in glycolysis uncoupled from oxidation. Then the in- sis, NADH and Ca2+ overload termediate of glycolysis accumulated, including lactate, protons and NDAH. during ischemic. Intracellular impair the activity of Na+/K+ ATPase, which extrudes + + + 3Na ions in exchange for 2K ions, leads to intracellular Na overload, sub- Reperfusion sequently activation of Na+/Ca2+ exchangers, results in intracellular Ca2+ overload. Excess NADH in enter the mitochondria membrane through malate/aspartate shuttle. Moreover, ischemic succinate accumu- At reperfusion, the rates of lation arises from reversal of succinate , which is driven by glucose oxidation, cardiac effi- fumarate overflow from purine break down and partial reversal ciency, and mechanical func- of the malate/aspartate shuttle. Green arrow means normal physiological tion remain depressed [40. process. Red arrow means pathophysiological process. Red X mark means 41]. The accelerated rates of the pathway is inhibited. glycolysis during ischemic pe- riod can resolve during reper- ensitize peripheral insulin [27-29]. Meanwhile, fusion, but still remain uncoupled from glucose plasma levels of hydrocortisone elevate, which oxidation (Figure 2) [42-44]. Furthermore, as also desensitize insulin [30]. All these effects reperfusion rapidly normalizes extracellular pH, promote lipolysis that leads to it generates a large trans-sarcolemmal proton increase plasma concentrations of FFA and gradient that increases Na+/H+ exchange and increase delivery of FFA to the myocardium. The exacerbates intracellular Na+ overload followed increased delivery of FFA to the myocardium ischemia. In return, Na+ overload promotes can alter fatty acid utilization during both isch- reverse activation of the Na+/Ca2+ exchanger, emia, and reperfusion following ischemia. thereby contributing to intracellular Ca2+ over- load and aggravation during reperfusion [45]. Although ATP production from glycolysis may be These disturbances in ionic dur- sufficient to maintain ionic homeostasis during mild to moderate ischemia, the of ing ischemia and during reperfusion contribute ATP derived from glycolysis uncoupled from to the deficits in both cardiac function and car- subsequent pyruvate oxidation results in the diac efficiency, both of which can be improved increased generation of lactate, protons and by therapies that correct myocardial energy nicotinamide adenine dinucleotide (NDAH) [31- production. By activating the PDC, by products 33]. Intracellular acidosis impair the activity of accumulation can be limited, and cardiac func- Na+/K+ ATPase [34], which leads to intracellular tional recovery is improved. Improving the cou- Na+ overload and subsequent activation of Na+/ pling of glucose metabolism by stimulating glu- Ca2+ exchangers. Also, impaired activity of the cose oxidation accelerates the recovery of PH sarcolemmal and sarcoplasmic Ca2+ ATPase and improves both cardiac mechanical function which are responsible for the extrusion and and cardiac efficiency [44].

61 Int J Clin Exp Med 2018;11(1):59-68 Glycolysis and fatty acid β-oxidation disorder in IR

theyenhance oxygen efficien- cy during myocardial ischemic [48, 49].

Succinate accumulates and reverse electron transport chain

Accumulation of the Krebs cy- cle intermediate succinate is a universal metabolic marker of ischemia due to its role in tissues arrangement and mi- tochondrial ROS production during reperfusion. Most im- portantly, succinate accumu- lation arises from reversal of succinate dehydrogenase un- Figure 2. Alterations of glucose and fatty acid β-oxidation metabolism in re- der ischemic conditions, wh- perfusion. At reperfusion, fatty acid β-oxidation is rapidly recovered due to the sudden restore of oxygen, with rates exceeding pre-ischemic levels. The ich in turn is driven by fum- combination of high-circulating fatty acid levels and a decrease in malonyl arate overflow from purine CoA control of mitochondrial fatty acid uptake results in the preferential use nucleotide break down and of fatty acids as an oxidative substrate over glucose at reperfusion. High partial reversal of the malate/ fatty acid oxidation rates still inhibit glucose oxidation. Most importantly, the aspartate shuttle [50]. Elev- accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochon- ated NADH level in the cyto- drial complex I in the first few minutes. MPTP opening because of ROS burst plasm that traveled out from and Ca2+ overload. Green arrow means normal physiological process. Red mitochondria during glycolysis arrow means pathophysiological process. Red X mark means the pathway relies on malate aspartate is inhibited. shuttle in cardiomyocyte [51]. Deamination of aspartate to Paradoxically, fatty acid β-oxidation is rapidly oxaloacetate transfers electrons from NADH in recovered at reperfusion, due to the sudden the to form malate. The malate in the restore of oxygen, with its rates exceeding pre- cytosol is then exchanged with mitochondrial ischemic levels [46]. The combination of high- succinate through dicarboxylate carrier [52]. circulating fatty acid levels with decreased Once in the matrix, the succinate fails to form malonyl CoA mitochondrial fatty acid uptake succinyl CoA due to the lack of CoA and GTP results in the preferential use of fatty acids as during ischemia. In parallel, AMPs, which accu- an energy source over glucose at reperfusion. mulates during ischemia, was metabolized into High fatty acid oxidation rates also inhibit glu- fumarate through purine nucleotide cycle [53]. cose oxidation. Because the regulation of malo- This fumarate can then be hydrolyzed to malate nyl CoA levels is central in administration of the by cytosolic fumarate hydratase. rate of fatty acid β-oxidation in the heart, MCD may play a major role in controlling the extent of After reperfusion, the accumulated succinates ischemic injury by promoting glucose oxidation. are rapidly re-oxidized by succinate dehydroge- This hypothesis was proved by the study that nase, which drives extensive ROS generation MCD inhibitors can increase myocardial malo- by reverse electron transport (RET) at mito- nyl CoA levels, decrease fatty acid β-oxidation, chondrial complex I in the first few minutes [54, accelerate glucose oxidation in both in vitro 55]. Under physiological condition, transpo- and in vivo [47]. This suggests that switching tation of electron across the differences in in energy substrate preference improves cardi- reduction potential between the NAD+/NADH ac function during and after ischemia. Per- and the Coenzyme Q (CoQ) pool across com- hexiline, trimetazidine, ranolazine, and etomox- plex I (ΔEh) has to be sufficient to pump prot- ir, all stimulate glucose metabolism while down ons across the mitochondrial inner membrane regulate free-fatty-acid metabolism. Therefore, against the proton motive force, Δp [56]. As

62 Int J Clin Exp Med 2018;11(1):59-68 Glycolysis and fatty acid β-oxidation disorder in IR

specific pathway through wh- ich AMPK works seems am- biguous in the previous lite- ratures. AMPK is a heterotrim- eric complex, and composed of a catalytic α-subunit com- prising a typical Ser/Thr kin- ase domain and regulatory β and γ subunits [63]. Each subunit has multiple isoforms (α1 and α2, β1 and β2, and γ1, γ2, and γ3) with tissue- Figure 3. Role of AMPK in ischemic reperfusion injury. Ca2+-dependent path- specific distribution. In heart, way mediated by CaMKKβ and an AMP-dependent pathway mediated by all isoforms have been report- liver kinase B1 (LKB1) can activate AMPK. Firstly, activated AMPK promote glucose utilization. AMPK stimulate glucose uptake by translocating GLUT4- ed to be expressed [64]. The containing intracellular vesicles across the plasma membrane by phosphor- α-subunit of AMPK is a 63- ylating PKC and p38MAPK/TAB1 pathway. Besides, AMPK promotes glycoly- kDa protein that exhibits ca- sis by increasing PFK2 activity. Secondly, AMPK inhibits FA synthesis while talytic activity. The α1 isoform increase Fatty acid oxidation through PGC1α/PPAR pathway. is widely expressed, whereas the α2 isoform has its highest four protons are pumped for every two elec- levels of expression in liver, heart, and skele- trons that pass through complex I, 2ΔEh > 4Δp tal muscle. The β and γ subunits appear to is requirement for the forward reaction to oc- be important in substrate specificity and ma- cur [57]. Electrons can be driven backward intenance of heterotrimer stability [65]. The from the CoQ pool onto the FMN of complex I, β-subunit acts as a scaffold for the binding of reduces the FMN which can donate a pair of the α- and γ-subunits and, by virtue of having a electrons to NAD+ to form NADH, or pass one carbohydrate binding module (CBM), also func- electron to oxygen to generate superoxide. The tion in the regulation of glycogen metabolism condition to be met for RET to occur is 4Δp > 2 [66]. The γ-subunit containing four cystathio- ΔEh [58]. The rapid oxidation of the succinate nine-b-synthase (CBS) domains, that serve to that accumulates during ischemia favors re- bind adenine and has also been duction of the CoQ pool, thereby maintaining a implicated in regulating glycogen metabolism, large ΔEh [59]. The reduced CoQ pool also since mutations in the CBS domains lead to favors proton pumping by complexes III and altered glycogen metabolism in both skeletal IV helping maintain a large Δp upon reperfu- muscle and heart. sion [60]. In addition, the degradation of ade- nine nucleotides during ischemia limits ADP The mechanism of AMPK activation involves 2+ availability upon reperfusion that would other- two distinct signals: a Ca -dependent pathway wise diminish Δp by stimulating ATP synthesis. mediated by CaMKKβ and an AMP-dependent In this scenario accumulated succinate act as pathway mediated by liver kinase B1 (LKB1) electron sink during ischemia, which is then (Figure 3) [67]. Theupstream phos- used to drive ROS by RET at complex I upon phorylated at Thr172 on α subunit, stimulate reperfusion. Excessive ROS will bring further allosteric effect upon binding of AMP within damage to the mitochondrial, such as Mito- the CBS domain of the γ subunit, thereby main- chondrial Permeability Transition Pore (MPTP) taining the enzyme in the activated state, as opening. well as protecting Thr172 from dephosphoryla- tion [68]. Thus, AMPK serves as a unique meta- AMPK signaling in IR bolic control node as it senses cellular energy status through modulation of its activities via AMPK, known as energy sensor, has been and allosteric activation by reported to be related to ischemic reperfusion AMP [69]. Numerous pathological processes injury. Intrinsic modulation of AMPK is critical have been shown to stimulate AMPK, including to prevent irreversible mitochondrial damage conditions that lead to alterations of the intra- and myocardial injury [61, 62]. However, the cellular AMP/ATP ratio (e.g., hypoxia, glucose

63 Int J Clin Exp Med 2018;11(1):59-68 Glycolysis and fatty acid β-oxidation disorder in IR deprivation) and calcium overload, which are AMPK activation is harmful for cardiomyocytes. the notable symptoms in ischemic reperfusion Since high rates of fatty acid oxidation can con- injury [70, 71]. tribute to ischemic damage by inhibiting glu- cose oxidation, it is important to maintain prop- Once AMPK activated, cardiomyocytes con- er control of fatty acid oxidation both during ducted energy consumption rather than reser- and following ischemic. vation, which means overwhelms . On one hand, AMPK promotes glu- Conclusion and future perspective cose utilization. AMPK stimulates glucose up- take by translocating GLUT4-containing intra- In the present review, we analyzed the altera- cellular vesicles across the plasma membrane tions of glucose and fatty acid β-oxidation dur- [72]. AMPK involves phosphorylation and acti- ing IR, as well as the role of AMPK signaling. In vation of Akt substrate of 160 kDa [73], protein brief, glucose uncoupled from oxidation due to kinase C [74], endothelial nitric oxide synthase high rates of fatty acid β-oxidation result in [75] and p38 mitogen-activated protein kinase/ intermediate metabolites, which are the main transforming growth factor β-activated protein pathogenic factor of reperfusion during isch- complex 1 [76], regulate GLUT4 translocation emic. In this case, glycolysis is the leading to the plasma membrane. Besides, AMPK pro- cause of IR injury. For this reason, the inhibition motes glycolysis by increasing phosphofructo- of glycolysis during ischemia will lessen lactate kinase 2 activity [77, 78], which produces fruc- and proton production, and improve cardiac tose 2, 6-bisphosphate, a potent stimulator of efficiency [80]. Previous clinical studies focused glycolysis. On the other hand, AMPK inhibits FA on inhibiting fatty acid oxidation and increasing synthesis while increase Fatty acid oxidation. glucose oxidation during ischemic heart dis- The phosphorylation process of acetyl-coA car- ease, but barely no study paid attention to the boxylase 1, which catalyzes the rate-limiting metabolites of glycolysis. Since AMPK signaling step in and sterol regulato- has dual effect in regulating glucose and fatty ry element-binding protein 1c, a transcription acid metabolism, we need to elucidate the pre- factor that promotes the expression of multi- cise molecular pathway when we want to inhibit ple lipogenic enzymes were inhibited. While glycolysis and promote glucose oxidation. Also, fatty acid uptake is increased by promoting the decreasing ischemic succinate accumulation translocation of fatty acid transporter CD36 to by pharmacological inhibition is sufficient to the plasma membrane, the mechanism under- ameliorate in vivo IR injury in murine models of lying this is unclear. In cytoplasm, fatty acids heart attack and stroke. In the future, we hope are transported into the mitochondria for more studies will focus on the bad influence of β-oxidation by CPT-1. AMPK activation enh- glycolysis and try everything to eliminate it in ances PGC-1a transcription [79], which incre- the ischemic reperfusion process. ases CPT-1 activity and activates fatty acid β-oxidation by inhibiting phosphorylation of Acknowledgements ACC2. ACC2 is localized to the outer membrane of the mitochondria near CPT-1 where it inhibits This work was supported by the National Na- production of malonyl-CoA, a potent allosteric tural Science Foundation of China (81503504, inhibitor of CPT-1. 81573733, 830472117, 81202797).

During ischemic, high AMP/ATP rate activates Disclosure of conflict of interest AMPK, which exerts catabolism to produce more ATP for cardiomyocytes utilization. Glyco- None. lysis dominates the main ATP production way Address correspondence to: Dr. Xijuan Jiang, Sc- due to lack of oxygen. In this point, AMPK hool of Integrative Medicine, Tianjin University presents beneficial effect for cardiomyocytes. of Traditional Chinese Medicine, 88th Yuquan However, during reperfusion, AMPK also pro- Road, Nankai District, Tianjin, China. Tel: +86-22- motes high rate of fatty acid β-oxidation, si- 59596287; E-mail: [email protected] nce oxygen content suddenly recover. In return, the increased rate of fatty acid β-oxidation References can inhibit glucose oxidation, which leads to increase lactate and proton production and [1] Lopaschuk GD, Ussher JR, Folmes CD, Jaswal decrease cardiac efficiency. In this situation, JS, Stanley WC. Myocardial fatty acid metabo-

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