Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly—Rescue by Specific Amino Acid Supplementation

Abstract

The heart is metabolically flexible. Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent/human cardiomyocytes. 3-β-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option.

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

“…Exogenous infusion of acetoacetate has been shown to inhibit the utilization of FFAs by the heart and results in an increase in the respiratory quotient of the heart [ 23 ]. Exposure of myocardial cells to ketone bodies diminishes insulin sensitivity and systolic cardiac function [ 24 ].…”

“…The heart has metabolic flexibility. Under normal circumstances, it mostly utilizes lipids and glucose for the generation of energy [ 24 ]. In uncontrolled diabetes, the heart shifts its metabolism towards the utilization of lipids predominantly, which, however, in the long term may turn out to be deleterious to LV function.…”

“…Lipid-induced v-ATPase disassembly is counter-balanced by the accumulation and stock of specific amino acids. A study examined the influence of ketone bodies on v-ATPase assembly status and control of lipid metabolism in rodent/human myocardial cells [ 24 ]. Exposure to β-OHB triggered v-ATPase disassembly and the ensuing events led to systolic dysfunction and insulin resistance, akin to a state of excessive lipid supply.…”

The cytosolic N-terminal domain of V-ATPase a-subunits is a regulatory hub targeted by multiple signals

“…In cardiomyocytes, V-ATPases in the early endosome disassemble in response to lipid overload, resulting in endosome alkalinization, relocalization of the fatty acid transporter CD36 to the plasma membrane, and further uptake of extracellular lipids (Liu et al, 2017). This process is highly significant, as it appears to be an early step in insulin resistance and ultimately cardiac contractile dysfunction (Liu et al, 2017) ( Wang et al, 2022). In cultured cells, promoting V-ATPase reassembly restored endosomal CD36 localization and reduced lipid uptake (Wang et al, 2021;.…”