The Heart has Intrinsic Ketogenic Capacity that is Facultatively Upregulated in Heart Failure with Preserved Ejection Fraction

Abstract

Heart Failure with preserved Ejection Fraction or ‘HFpEF’ is now the most common type of heart failure worldwide, with considerable morbidity and mortality, and with no effective pharmacotherapies. For the first time, we show that the human and murine HFpEF heart have impaired uptake of ketone bodies, and reveal an intrinsic capacity of human and murine hearts to generate their own ketones via the canonical rate-limiting ketogenic enzyme, 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2). We demonstrate that protein levels of HMGCS2 are dramatically elevated in HFpEF myocardium that does not overcome reduced specific activity of this enzyme. This appeared to be due to hyperacetylation caused by depletion of the de-acetylating enzyme sirtuin 3 and decreased oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio, upon which the deacetylation activity of sirtuins is dependent. Also for the first time, we show that the canonical stimuli that serve to turn on ketogenesis in the liver are present locally in the HFpEF heart, augmented by a profound energy deficiency as determined by depleted phosphocreatine/ adenosine triphosphate (PCr/ATP) ratio. Thus, metabolically inflexible HFpEF hearts try to auto-regulate their energy supply by upregulating ketogenesis as an apparent “rescue strategy”. These results serve to reframe our understanding of cardiac ketone metabolism and open opportunities for novel therapeutic strategies for HFpEF, urgently needed.

Emerging Roles of SIRT3 in Cardiac Metabolism

“…A recent study in cardiac hypertrophy reported SIRT3dependent enhancement of ketone body metabolism via AMPKmediated increase in the levels of monocarboxylic transporters 1 (MCT1) and 3-oxoacid CoA-transferase (OXCT1) (60). Another study reported that a key enzyme in ketogenesis, HMGS2 is dramatically upregulated in heart failure with preserved ejection fraction (HFpEF) (142). Its specific activity is, however, impaired in these hearts.…”

“…HFpEF myocardium is also characterized by a net reduction in NAD + /NADH ratio and subsequently in SIRT3 expression. Since ketogenesis may serve as an essential energy source in failing hearts, SIRT3-dependent upregulation of ketogenesis may function as a "rescue strategy" in heart failure (142,143).…”

Beta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator

“…Fragmentary extrahepatic ketogenesis has been reported in tumour cells ( 43 ), astrocytes of the central nervous system (CNS) ( 44 ), renal cells ( 45 ), retinal pigment epithelium ( 46 ), or other cells with an unusual expression of mHMGCS2 ( 47 , 48 ), ketogenesis was also observed. However, in the physiological state, no extrahepatic tissue presents a higher steady-state ketone body concentration than in the circulation ( 49 ), indicating that the extrahepatic ketogenesis does not influence the circulating ketone body concentration.…”