bims-hafaim 2024-02-25 papers

Issue of 2024–02–25
four papers selected by
Kyle McCommis, Saint Louis University

Metabolism. 2024 Feb 17. pii: S0026-0495(24)00044-1. [Epub ahead of print]154 155818

Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.

Simran Pherwani, David Connolly, Qiuyu Sun, Qutuba G Karwi, Michael Carr, Kim L Ho, Cory S Wagg, Liyan Zhang, Jody Levasseur, Heidi Silver, Jason R B Dyck, Gary D Lopaschuk.

BACKGROUND: Cardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production.
METHODS: 8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac energy metabolism was measured in isolated working hearts perfused with 5 mM glucose, 0.8 mM palmitate, and either 0.2 mM or 0.6 mM β-hydroxybutyrate (βOHB).
RESULTS: TAC hearts had significantly decreased %EF compared to sham hearts, with no effect of DAPA. Glucose oxidation was significantly decreased in TAC hearts compared to sham hearts and did not decrease further in TAC hearts treated with high βOHB or in TAC DAPA hearts, despite βOHB oxidation rates increasing in both TAC vehicle and TAC DAPA hearts at high βOHB concentrations. Rather, increasing βOHB supply to the heart selectively decreased fatty acid oxidation rates. DAPA significantly increased ATP production at both βOHB concentrations by increasing the contribution of glucose oxidation to ATP production.
CONCLUSION: Therefore, increasing ketone concentration increases energy supply and ATP production in HFrEF without further impairing glucose oxidation.

Keywords: HFrEF; Ketone oxidation; SGLT2 inhibition

DOI: https://doi.org/10.1016/j.metabol.2024.155818

Biochem J. 2024 Feb 23. pii: BCJ20230421. [Epub ahead of print]

Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.

Jackson E Stewart, Jenna M Crawford, William E Mullen, Angelica Jacques, Michael W Stoner, Iain Scott, Dharendra Thapa.

Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging and many age-related conditions. As such, complete control of mitochondrial function is critical to maintain cardiac efficiency in the aged heart. Lysine acetylation is a reversible post-translational modification shown to regulate several mitochondrial metabolic and biochemical processes. In the present study, we investigated how mitochondrial lysine acetylation regulates fatty acid oxidation and cardiac function in the aged heart. We found a significant increase in mitochondrial protein acetylation in the aged heart which correlated with increased level of mitochondrial acetyltransferase-related protein GCN5L1. We showed that acetylation status of several fatty acid and glucose oxidation enzymes (long-chain acyl-CoA dehydrogenase, hydroxyacyl-coA dehydrogenase, and pyruvate dehydrogenase) were significantly upregulated in aged heart which correlated with decreased enzymatic activities. Using a cardiac-specific GCN5L1 knockout animal model, we showed that overall acetylation of mitochondrial proteins was decreased in aged knockout animals, including fatty acid oxidation proteins which led to improved fatty acid oxidation activity and attenuated cardiac diastolic dysfunction observed in the aged heart. Together, these findings indicate that lysine acetylation regulates fatty acid oxidation in the aged heart which results in improved cardiac diastolic function and this is in part regulated by GCN5L1.

Keywords: aging; cardiac function; fatty acid oxidation; lysine acetylation; mitochondria

DOI: https://doi.org/10.1042/BCJ20230421

J Adv Res. 2024 Feb 19. pii: S2090-1232(24)00077-8. [Epub ahead of print]

AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis.

Wuping Tan, Yijun Wang, Siyi Cheng, Zhihao Liu, Mengjie Xie, Lingpeng Song, Qinfang Qiu, Xiaofei Wang, Zeyan Li, Tianyuan Liu, Fuding Guo, Jun Wang, Xiaoya Zhou.

INTRODUCTION: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis.
OBJECTIVES: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model.
METHODS: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods.
RESULTS: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively.
CONCLUSIONS: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Keywords: AdipoRon; Fatty acid oxidation; Heart failure with preserved ejection fraction; Lipid accumulation; Metabolic syndrome

DOI: https://doi.org/10.1016/j.jare.2024.02.015

Diabetes. 2024 Feb 22. pii: dbi230019. [Epub ahead of print]

Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of its Pathology.

Lisa C Heather, Keshav Gopal, Nikola Srnic, John R Ussher.

Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases the risk of a specific form of cardiomyopathy referred to as diabetic cardiomyopathy (DbCM), originally defined as ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. Herein, we provide an overview on the key mediators of DbCM, with an emphasis on the role for perturbations in cardiac substrate metabolism. We discuss key mechanisms regulating metabolic dysfunction in DbCM, with additional focus on the role of metabolites as signalling molecules within the diabetic heart. Furthermore, we discuss the preclinical approaches to target these perturbations to alleviate DbCM. With several advancements in our understanding, we propose "diastolic dysfunction in the presence of altered myocardial metabolism in a person with diabetes, but absence of other known causes of cardiomyopathy and/or hypertension", as a new definition for, or approach to classify, DbCM. However, we recognize that no definition can fully explain the complexity of why some individuals with DbCM exhibit diastolic dysfunction, whereas others develop systolic dysfunction. Due to DbCM sharing pathological features with heart failure with preserved ejection fraction (HFpEF), the latter of which is more prevalent in the diabetic population, it is imperative to determine whether effective management of DbCM decreases HFpEF prevalence.

DOI: https://doi.org/10.2337/dbi23-0019