ReviewMetabolic reprogramming of the heart through stearoyl-CoA desaturase
Introduction
Myocardial metabolism plays an important role in maintaining proper heart function and therefore is strictly regulated. Under aerobic conditions, the heart derives 60–90% of the energy necessary for contractile function from fatty acid (FA) oxidation, whereas the remainder is obtained mainly from carbohydrates (glucose and lactate) [1], [2]. Evidence suggests that impaired cardiomyocyte metabolism contributes to contractile dysfunction and the progressive left-ventricular remodeling that is characteristic of heart failure. In disease states, such as ischemia-reperfusion, diabetes, and obesity, cardiac substrate utilization shifts to the excessive use of FAs in place of glucose [1], [2], [3]. This shift in metabolism has been suggested to play a role in the development of cardiomyopathy, leading to both impaired contractile function and ischemic injury [2], [4]. In contrast, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation leads to ischemia resistance in the heart [5] and protects against lipotoxic heart disease [6]. Patients with congenital lipodystrophy, a rare disorder in which the absence of adipocytes results in the accumulation of lipid in non-adipose tissues, or with inherited mitochondrial fatty acid oxidation defects develop premature cardiomyopathy [7]. In animal models of obesity and diabetes, such as leptin-deficient ob/ob mice, leptin receptor-deficient db/db mice and Zucker Diabetic Fatty rats, lipid accumulation within cardiomyocytes and dysregulation in cardiac metabolism are associated with impaired contractile function [7]. To date, metabolic alterations in the failing heart have been considered a part of the phenotype (i.e., a consequence of the development of cardiac dysfunction). However, some observations suggest the intriguing possibility that the disruption of normal glucose or FA metabolism may indeed be a primary factor responsible for the development of heart failure. Thus, understanding the regulatory mechanisms that are responsible for reprogramming cardiomyocyte metabolism is imperative to discover new treatments to improve cardiac function.
Many studies underscore the important role of lipogenic enzymes in the regulation of cardiac metabolism and function and suggest that the role of lipogenic genes in cardiomyocytes may be distinct from other tissues. Cardiac sterol regulatory element-binding protein 1 (SREBP1), a key lipogenic transcription factor, was shown to activate G-protein-coupled inwardly reflecting K+ channels, leading to enhanced acetylcholine-sensitive K+ currents and reduced arrhythmias postmyocardial infraction [8]. The transgenic overexpression of fatty acid transport protein 1 (FATP1) in the heart has also been shown to cause lipotoxic cardiomyopathy [9]. The heart-specific knockdown of peroxisome proliferator-activated receptor γ (PPARγ) [10] and acyl-CoA synthase 1 (ACS-1) [11] induces cardiac hypertrophy. Fatty acid synthase (FAS), the enzyme that catalyzes de novo FA synthesis, is involved in the regulation of the ability of the heart to respond to stress through the activation of Ca2+/calmodulin-dependent protein kinase II [12]. Diacylglycerol acyltransferase 1 overexpression improves heart function in long-chain acyl-CoA synthetase-expressing mice, which develop lipotoxic cardiomyopathy, by reducing the levels of cardiac ceramide and diacylglycerol (DAG), decreasing cardiomyocyte apoptosis, but increasing FA oxidation [13].
Recent studies showed that stearoyl-CoA desaturase (SCD), an enzyme involved in the biosynthesis of monounsaturated fatty acids (MUFAs), induces the reprogramming of cardiomyocyte metabolism, thereby playing an important role in the regulation of cardiac function [6], [14], [15]. The lack of SCD1 expression decreases FA uptake and oxidation and increases glucose transport and oxidation in the heart [14]. Disruption of the SCD1 gene improves cardiac function in obese leptin-deficient ob/ob mice by correcting systolic and diastolic dysfunction [6]. The improvement is associated with a reduction of the expression of genes involved in FA transport and lipid synthesis within the heart, together with decreases in cardiac free fatty acid (FFA), DAG, triacylglycerol (TG), and ceramide levels and reduced cardiomyocyte apoptosis [6]. Additionally, recent studies showed that physiological hypertrophy induced by endurance training is accompanied by the increased expression of SCD1 and SCD2 [15]. Here, we review recent advances in understanding the role of SCD in the control of heart metabolism and its involvement in the pathogenesis of lipotoxic cardiomyopathy.
Section snippets
Stearoyl-CoA desaturase (SCD): what does it do?
SCD is the rate-limiting enzyme that catalyzes the synthesis of MUFAs, mainly oleate and palmitoleate (Fig. 1), which are used as substrates for the synthesis of TG, wax esters, cholesteryl esters, and phospholipids (PLs) [16]. The degree of the unsaturation of cellular lipids can also play a role in membrane fluidity and cell signaling. Therefore, SCD is highly conserved, with multiple isoforms that provide overlapping but distinct tissue and substrate specificity. Four isoforms of SCD have
Isoforms of SCD expressed in the heart
Three SCD isoforms (SCD1, SCD2, and SCD4) are expressed in the mouse heart. The expression of SCD1 is several times higher in the murine heart compared with SCD4 [6], [20]. However, SCD4 expression is significantly increased after a high-fat diet in obese leptin-deficient mice [6], [20] and in states of SCD1 deficiency [14], [20]. Cardiac SCD4 cDNA encodes a 353-amino-acid residue protein with four transmembrane regions that is more than 80% homologous to the other three mouse SCD genes [20].
Role of SCD in cardiac metabolism and function: what we have learned from SCD1 knockout mice
Studies on mouse strains that have a mutation in the SCD1 gene have provided evidence that SCD1 is an important control point in lipid metabolism and body weight regulation [24], [27], [31]. Mice with targeted disruption of the SCD1 gene exhibited increased energy expenditure, reduced body adiposity, and increased insulin sensitivity and are resistant to diet-induced obesity [16], [40], [33]. SCD1 was found to be specifically repressed during leptin-mediated weight loss, and leptin-deficient
SCD1 deletion improves heart function in obese mouse models
The ectopic deposition of lipids in the myocardium may lead to functional impairments, as observed in obese leptin-resistant Zucker diabetic rats (ZDF) [53], db/db mice, and leptin-deficient ob/ob mice [54]. Ob/ob mice develop pathologic LV hypertrophy, together with elevated TG content and increased cardiomyocyte apoptosis [20], [54]. Numerous studies have suggested an important role for SCD in the pathogenesis of lipid-induced heart disease. SCD1 expression and activity are significantly
SCD1 and cardiomyocyte apoptosis
Excessive deposition of intramyocardial TG enlarges the intracellular pool of fatty acyl-CoA, thereby providing a substrate for nonoxidative metabolic pathways, such as ceramide synthesis [61]. Increased levels of ceramide cause apoptosis of cardiac myocytes, which can result in LV chamber expansion, contractile dysfunction, and impaired diastolic filling, contributing to the cardiomyopathy observed in states of obesity and diabetes [53]. This phenomenon, broadly referred to as “cardiac
Physiological and pathological left ventricular hypertrophy: role of SCD and lipid metabolism
Cardiac hypertrophy is associated with extensive remodeling, which eventually will affect cardiac function and ultimately contribute to the transition from compensatory hypertrophy to cardiac failure [72]. Both physiological and pathological cardiac hypertrophy causes changes in lipid metabolism in the heart, although little is known about the underlying molecular changes. Previous studies have primarily focused on the FA oxidation pathway and reported the downregulation of genes involved in FA
Regulation of cardiac metabolism and function by oleic acid
Dietary stearic acid intake ranks second among the SFA consumed in the United States, accounting for 25.8% of SFA intake and 2.9% of total kcal [85]. Stearate is a precursor for the endogenous synthesis of oleate by SCD [28]. Oleic acid is the most relevant intermediate between SFA and PUFA, and it is best suited for storage or incorporation into glycerolipids and modulation of the basic features of biomembranes [86]. Because of its unique features, oleate plays an important metabolic role in
Plasma desaturation index as a predictor of cardiac health in human
The role of SCD1 in human heart function and heart health has not been investigated directly, rather the MUFA to SFA ratios in plasma and the risk of cardiovascular disease (CVD) has been explored. Warensjo et al. [102] showed that the plasma SCD desaturation index is elevated by a diet that is high in saturated fat compared with a diet that is rich in unsaturated fat. The FA composition of plasma cholesteryl esters was evaluated in relation to CVD and total mortality in over 2000 individuals
SCD and atherosclerosis
Atherosclerosis is a multifactorial complex disease, which is responsible for approximately 50% of deaths in Western world, mainly due to CVD, including heart disease and stroke [110]. Risk factors for the development of atherosclerotic diseases include diabetes, hypertension, hyperlipidemia, and a lack of physical activity [111]. Interestingly, although SCD1 deficiency reduces plasma TG and provides protection from obesity and insulin resistance [16], [27], [40], which would be predicted to be
Conclusion and future direction
SCD, a central enzyme in lipid metabolism that synthesizes MUFAs, could be considered a house-keeping enzyme because its main product, oleate, is abundant in many dietary sources and tissue lipids. However, research over the past decade has identified SCD as an important regulator of tissue metabolism and provided evidence that SCD, in fact, is a key regulatory enzyme of body adiposity and insulin signaling. Furthermore, recent studies showed that SCD has the ability to reprogram cardiac
Conflict of interest
The authors declare that there are no conflicts of interest.
Transparency Document
Acknowledgements
P. Dobrzyn is supported by Grants from by the National Science Centre (UMO-2011/01/D/NZ3/04777) and National Centre for Research and Development (LIDER/19/2/L-2/10/NCBiR/2011). A. Dobrzyn is supported by a Grant from the Foundation For Polish Science (TEAM/2010-5/2).
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2024, Biochimica et Biophysica Acta - Molecular Cell ResearchSalvia miltiorrhiza and Pueraria lobata, two eminent herbs in Xin-Ke-Shu, ameliorate myocardial ischemia partially by modulating the accumulation of free fatty acids in rats
2021, PhytomedicineCitation Excerpt :It has been reported that palmitic acid can activate the NF-κB pathway, stimulate inflammatory responses, upregulate the expression of proinflammatory factors (TNF-α and IL-6) in N42 hypothalamic cells (Sergi et al., 2018), and promote the accumulation of the toxic metabolite ceramide (Palomer et al., 2018). Palmitic acid also activates the activities of caspase-3 and caspase-7 in cardiomyocytes and promotes apoptosis (Dobrzyn et al., 2015). Oleic acid, a vital intermediate between saturated FFAs and polyunsaturated FFAs, is suitable for storage or incorporation into glycerides.
Consumption of clarified goat butter added with turmeric (Curcuma longa L.) increase oleic fatty acid and lipid peroxidation in the liver of adolescent rats
2021, Food BioscienceCitation Excerpt :This reaction involves cytochrome b5, cytochrome b5 reductase, NADPH and oxygen molecules (Manabu et al., 2004). MUFA are used in the synthesis of triglycerides, cholesterol esters and phospholipids (Dobrzyn et al., 2015). Palmitic acid (16:0) is the main precursor to the biosynthesis of new fatty acids.
EGCG regulates fatty acid metabolism of high-fat diet-fed mice in association with enrichment of gut Akkermansia muciniphila
2020, Journal of Functional FoodsCitation Excerpt :However, EGCG did not affect the stearic acid (C18:0) concentration in the sera when compared with the mice fed with HFD alone. After absorbed primarily in duodenum, the stearic acid (SA, 18:0) can be desaturated to oleic acid (OA, 18:1n-9) by stearoyl-CoA desaturases (SCD) (Dobrzyn, Bednarski, & Dobrzyn, 2015), and SCD index (16:1/16:0) acts as biomarker of estimated SCD activity (Lv et al., 2018). In our study, EGCG treatment in mice numerically decreased the SCD index, and depressed the SCD1 protein expression in the liver.
Protein engineering: Regulatory perspectives of stearoyl CoA desaturase
2018, International Journal of Biological MacromoleculesCitation Excerpt :Insulin resistance and obesity are directly related to activation or overexpression of SCD-1. It has been proved that inhibiting insulin signaling leads to the accumulation of lipids in insulin-sensitive organs instead of lipid accumulation in the adipocytes [9]. SCD-1 activation produced a high amount of triglycerides (TGS) which have extra lipogenic influence in adipose tissues [10].