Abstract 4344227: Flux Balance Analysis Predicts Cardio-Metabolic Benefits of Food Products in Cancer Patients

ABSTRACTIntroduction: Obesity is recognized as a risk factor for cardiovascular disease, expending independent adverse effects on the cardiovascular system. This relationship is complex due to several associations with cardiovascular disease risk factors/markers such as hypertension, dyslipidemia, insulin resistance/dysglycemia, or type 2 diabetes mellitus. Obesity induces a variety of cardiovascular system structural adaptations, from subclinical myocardial dysfunction to severe left ventricular systolic heart failure. Abnormalities in cardiac metabolism and subsequent cardiac energy, have been proposed as major contributors to obesity-related cardiovascular disease. Ectopic fat depots play an important role in several of the hypotheses postulated to explain the association between obesity, cardiac metabolism and cardiac dysfunction.Areas covered: In this review, we addressed with contemporary studies how obesity-associated metabolic conditions and ectopic cardiac fat accumulation, translate into cardiac energy metabolism disturbances that may lead to adverse effects on the cardiovascular system.Expert commentary: Obesity and ectopic fat accumulation has long been related to metabolic diseases and adverse cardiovascular outcomes. Recent imaging advances have just started to address the complex interplays between obesity, ectopic fat depots, cardiac metabolism and the risk of obesity-related cardiovascular disease. A better comprehension of these obesity-associated metabolic disturbances will lead to earlier detection of patients at increased risk of cardiovascular disease and to the development of novel therapeutic metabolic targets to treat a wide variety of cardiovascular diseases.

In lower eukaryotes, beta-oxidation of fatty acids is restricted primarily to the peroxisomes and the resultant acetyl-CoA molecules (and the chain-shortened fatty acids) are transported via the cytosol into the mitochondria for further breakdown and usage. Using a loss-of-function mutation in the Magnaporthe grisea PEROXIN6 orthologue, we define an essential role for peroxisomal acetyl-CoA during the host invasion step of the rice-blast disease. We show that an Mgpex6Delta strain lacks functional peroxisomes and is incapable of beta-oxidation of long-chain fatty acids. The Mgpex6Delta mutant lacked appressorial melanin and host penetration, and was completely non-pathogenic. We further show that a peroxisome-associated carnitine acetyl-transferase (Crat1) activity is essential for such appressorial function in Magnaporthe. CRAT1-minus appressoria showed reduced melanization, but were surprisingly incapable of elaborating penetration pegs or infection hyphae. Exogenous addition of excess glucose during infection stage caused partial remediation of the pathogenicity defects in the crat1Delta strain. Moreover, Mgpex6Delta and crat1Delta mycelia showed increased sensitivity to Calcofluor white, suggesting that weakened cell wall biosynthesis in a glucose-deficient environment leads to appressorial dysfunction in these mutants. Interestingly, CRAT1 was itself essential for growth on acetate and long-chain fatty acids. Thus, carnitine-dependent metabolic activities associated with the peroxisomes, cooperatively facilitate the appressorial function of host invasion during rice-blast infections.

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1β. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long-chain fatty acid oxidation disorders (lcFAOD), we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss-of-function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. We report that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.

BackgroundWhile the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications.MethodsThis was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, 123I-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period.ResultsThe patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m2). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including β-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05).ConclusionsAlthough the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications.Clinical Trial Registration: UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257

The conundrum of whole foods versus macronutrient composition in assessing effects on insulin sensitivity

Obesity incidence has been increasing at an alarming rate, especially in women of reproductive age. It is estimated that 50% of pregnancies occur in overweight or obese women. It has been described that maternal obesity (MO) predisposes the offspring to an increased risk of developing many chronic diseases in an early stage of life, including obesity, type 2 diabetes, and cardiovascular disease (CVD). CVD is the main cause of death worldwide among men and women, and it is manifested in a sex-divergent way. Maternal nutrition and MO during gestation could prompt CVD development in the offspring through adaptations of the offspring’s cardiovascular system in the womb, including cardiac epigenetic and persistent metabolic programming of signaling pathways and modulation of mitochondrial metabolic function. Currently, despite diet supplementation, effective therapeutical solutions to prevent the deleterious cardiac offspring function programming by an obesogenic womb are lacking. In this review, we discuss the mechanisms by which an obesogenic intrauterine environment could program the offspring’s cardiovascular metabolism in a sex-divergent way, with a special focus on cardiac mitochondrial function, and debate possible strategies to implement during MO pregnancy that could ameliorate, revert, or even prevent deleterious effects of MO on the offspring’s cardiovascular system. The impact of maternal physical exercise during an obesogenic pregnancy, nutritional interventions, and supplementation on offspring’s cardiac metabolism are discussed, highlighting changes that may be favorable to MO offspring’s cardiovascular health, which might result in the attenuation or even prevention of the development of CVD in MO offspring. The objectives of this manuscript are to comprehensively examine the various aspects of MO during pregnancy and explore the underlying mechanisms that contribute to an increased CVD risk in the offspring. We review the current literature on MO and its impact on the offspring’s cardiometabolic health. Furthermore, we discuss the potential long-term consequences for the offspring. Understanding the multifaceted effects of MO on the offspring’s health is crucial for healthcare providers, researchers, and policymakers to develop effective strategies for prevention and intervention to improve care.

Carnitine-acylcarnitine translocase (CACT) deficiency is an inborn error of metabolism involving the mitochondrial beta-oxidation of long-chain fatty acids. The aim of this study was to report on a new case (neonatal phenotype) and review the literature data on 24 previously reported cases. Clinical data of the new case are described and compared with the previous reports. The patient with a novel mutation had clinical features and biochemical findings similar to those of the other reported patients. CACT is an entity in which clinical encephalopathy, hepatomegaly and arrythmias are common. Hyperammonaemia and elevation of creatine kinase seem to be constant findings as in other disorders of mitochondrial beta-oxidation of long-chain fatty acids. The mortality rate is very high.

The heart makes its living by liberating energy from a variety of oxidizable substrates, either simultaneously or vicariously.1 Because of built-in mechanisms that choose the most efficient substrate for a given physiological environment, the heart is a true metabolic omnivore.2 The link between metabolism and function of the heart was discovered by Langendorff3 when he demonstrated that the mammalian heart receives oxygen and nutrients through the coronary circulation and not through the endocardium, as it had been assumed until then. Early investigators also knew already that the heart oxidizes fatty acids and glucose,4 and myocardial fuel economy became a focus of biochemical investigation in the 1960s. Biochemists “discovered” the heart as a convenient bag of enzymes to study muscle metabolism and found that fatty acids suppress glucose oxidation, chiefly at the level of the pyruvate dehydrogenase complex.5 Conversely, we later found that glucose suppresses fatty acid oxidation,1 chiefly at the level of fatty acid entry into the mitochondria. In short, fuel metabolism in the heart is highly regulated, allowing the heart to respond to substrate availability, circulating hormones (such as insulin or catecholamines), coronary flow, and workload by choosing the “right” substrate at the right moment. Unless blood supply is curtailed, as it is the case in ischemia, the heart is never short of fuel to burn. See p 2125 What is, then, the principle that underlies substrate switching? As every nutritionist knows, fat has a higher caloric value than carbohydrates; at the same time, the oxidation of carbohydrates results in more efficient energy production than the oxidation of fat. The heart readily oxidizes both substances. Substrate switching in the heart is determined by an interaction of control and regulation of the metabolism of energy providing substrates. According to the metabolic control theory,6 …

Clinical Practice Guidelines for Healthy Eating for the Prevention and Treatment of Metabolic and Endocrine Diseases in Adults: Cosponsored by the American Association of Clinical Endocrinologists/The American College of Endocrinology and the Obesity Society Executive Summary

The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning.

Serelaxin (recombinant human relaxin-2) treatment affects the endogenous synthesis of long chain poly-unsaturated fatty acids and induces substantial alterations of lipidome and metabolome profiles in rat cardiac tissue

Background: Heart failure (HF) is a global health problem requiring more effective therapeutic alternatives. While HF involves disturbances in cardiac metabolism associated with lipidomic remodeling, there is a lack of approaches to specifically target cardiac metabolism. Recently, it has been shown in murine models of HF, that the use of nicotinamide riboside (vitamin B3) alone or the combination of B9 and B12 vitamins, before the development of HF, improved cardiac metabolism and function. Our hypothesis is that the combination of B3, B9 and B12 vitamins, used when HF is declared, will improve lipid metabolism, cardiac function and survival. The aim of this study is to evaluate the curative benefit of a synthetic diet enriched with the combination of these three vitamins (VitB) in a murine model of HF with reduced ejection fraction (EF). Method: Pressure overload was induced by constriction of the transverse aorta (TAC) in male and female mice. After 4 weeks, TAC mice reaching a pressure gradient of 60 mmHg, an increased left ventricle mass &gt;30% and a reduced EF &gt;10%, were randomized to a VitB-enriched diet or not. Results: In females, VitB improved survival and cardiac hypertrophy (-24%, p&lt;0.05) as well as EF (+22%, p&lt;0.01). We also observed a reduction of cardiac fibrosis emphasized by a significant decrease expression of collagen 1a and 3 (-30% and -19% respectively) and hydroxyproline concentration (-32%, p&lt;0.01). No benefit was observed in males in terms of survival, cardiac function and fibrosis. Untargeted mass spectrometry (MS)-based lipidomics on plasmas at 8 weeks of treatment showed a decrease in several individual triglycerides (TG from 43 to 48 %; p&lt;0.05) in TAC females that were normalized by VitB. In contrast, in TAC males, most of the annotated TGs were increased (from ̴35 to 210%; p&lt;0.05), a profile exacerbated upon VitB treatment. MSMS identification of TG side chains revealed a differential profile in terms of fatty acid composition according to sex and treatment. In VitB females, longer and polyunsaturated TGs (53 to 60C; 5 to 12 double bonds) were significantly increased (1.6- to 2.1-fold) while, in VitB males, the increased TGs (1.2- to 5.2-fold) were shorter (24C to 48C) and saturated (no double bonds). Conclusion: Our study pointed out a sexual dimorphism in the response to VitB treatment in HF in favor of females and implying a lipidomic remodeling promoting cardioprotective polyunsaturated TGs. European Research Area Network on Cardiovascular Diseases, Canadian Institutes of Health Research, Fonds de recherche du Québec - Santé. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

<i>Circulation Research</i> Thematic Synopsis

Road to trans-fat free Philippines: An emerging milestone amidst COVID-19 pandemic

Saccharomyces cerevisiae is an ideal model eukaryote for studying fatty-acid transport. Yeast are auxotrophic for unsaturated fatty acids when grown under hypoxic conditions or when the fatty-acid synthase inhibitor cerulenin is included in the growth media. The FAT1 gene encodes a protein, Fat1p, which is required for maximal levels of fatty-acid import and has an acyl CoA synthetase activity specific for very-long-chain fatty acids suggesting this protein plays a pivotal role in fatty-acid trafficking. In the present work, we present evidence that Fat1p and the murine fatty-acid transport protein (FATP) are functional homologues. FAT1 is essential for growth under hypoxic conditions and when cerulenin was included in the culture media in the presence or absence of unsaturated fatty acids. FAT1 disruptants (fat1Delta) fail to accumulate the fluorescent long-chain fatty acid fatty-acid analogue 4, 4-difluoro-5-methyl-4-bora-3a,4a-diaza-s-indacene-3-do decanoic acid (C1-BODIPY-C12), have a greatly diminished capacity to transport exogenous long-chain fatty acids, and have very long-chain acyl CoA synthetase activities that were 40% wild-type. The depression in very long-chain acyl CoA synthetase activities were not apparent in cells grown in the presence of oleate. Additionally, beta-oxidation of exogenous long-chain fatty acids is depressed to 30% wild-type levels. The reduction of beta-oxidation was correlated with a depression of intracellular oleoyl CoA levels in the fat1Delta strain following incubation of the cells with exogenous oleate. Expression of either Fat1p or murine FATP from a plasmid in a fat1Delta strain restored these phenotypic and biochemical deficiencies. Fat1p and FATP restored growth of fat1Delta cells in the presence of cerulenin and under hypoxic conditions. Furthermore, fatty-acid transport was restored and was found to be chain length specific: octanoate, a medium-chain fatty acid was transported in a Fat1p- and FATP-independent manner while the long-chain fatty acids myristate, palmitate, and oleate required either Fat1p or FATP for maximal levels of transport. Lignoceryl CoA synthetase activities were restored to wild-type levels in fat1Delta strains expressing either Fat1p or FATP. Fat1p or FATP also restored wild-type levels of beta-oxidation of exogenous long-chain fatty acids. These data show that Fat1p and FATP are functionally equivalent when expressed in yeast and play a central role in fatty-acid trafficking.