Showing papers by "Jan F. C. Glatz published in 2022"

CD36 (SR-B2) as master regulator of cellular fatty acid homeostasis

Abstract: Purpose of review Transmembrane glycoprotein cluster of differentiation 36 (CD36) is a scavenger receptor class B protein (SR-B2) that serves various functions in lipid metabolism and signaling, in particular facilitating the cellular uptake of long-chain fatty acids. Recent studies have disclosed CD36 to play a prominent regulatory role in cellular fatty acid metabolism in both health and disease. Recent findings The rate of cellular fatty acid uptake is short-term (i.e., minutes) regulated by the subcellular recycling of CD36 between endosomes and the plasma membrane. This recycling is governed by the activity of vacuolar-type H+-ATPase (v-ATPase) in the endosomal membrane via assembly and disassembly of two subcomplexes. The latter process is being influenced by metabolic substrates including fatty acids, glucose and specific amino acids, together resulting in a dynamic interplay to modify cellular substrate preference and uptake rates. Moreover, in cases of metabolic disease v-ATPase activity was found to be affected while interventions aimed at normalizing v-ATPase functioning had therapeutic potential. Summary The emerging central role of CD36 in cellular lipid homeostasis and recently obtained molecular insight in the interplay among metabolic substrates indicate the applicability of CD36 as target for metabolic modulation therapy in disease. Experimental studies already have shown the feasibility of this approach.

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.

Endosomal v-ATPase as a Sensor Determining Myocardial Substrate Preference

Abstract: The heart is a metabolically flexible omnivore that can utilize a variety of substrates for energy provision. To fulfill cardiac energy requirements, the healthy adult heart mainly uses long-chain fatty acids and glucose in a balanced manner, but when exposed to physiological or pathological stimuli, it can switch its substrate preference to alternative substrates such as amino acids (AAs) and ketone bodies. Using the failing heart as an example, upon stress, the fatty acid/glucose substrate balance is upset, resulting in an over-reliance on either fatty acids or glucose. A chronic fuel shift towards a single type of substrate is linked with cardiac dysfunction. Re-balancing myocardial substrate preference is suggested as an effective strategy to rescue the failing heart. In the last decade, we revealed that vacuolar-type H+-ATPase (v-ATPase) functions as a key regulator of myocardial substrate preference and, therefore, as a novel potential treatment approach for the failing heart. Fatty acids, glucose, and AAs selectively influence the assembly state of v-ATPase resulting in modulation of its proton-pumping activity. In this review, we summarize these novel insights on v-ATPase as an integrator of nutritional information. We also describe its exploitation as a therapeutic target with focus on supplementation of AA as a nutraceutical approach to fight lipid-induced insulin resistance and contractile dysfunction of the heart.

Subcellular Recycling of CD36 as Target to Rescue Lipid Overload‐induced Myocardial Contractile Dysfunction

Abstract: Disturbances in cardiac metabolism are increasingly being recognized as crucial drivers of the development and progression of heart disease and ageing. In particular, lipid overload due to Western life style or obesity eventually elicits cardiac insulin resistance and contractile dysfunction (referred to as diabetic cardiomyopathy). As a result, there is an urgent unmet clinical need for treatments that can directly target metabolic defects in heart failure. The transmembrane protein CD36 both facilitates myocardial fatty acid uptake and regulates this process by its subcellular recycling between endosomes and the sarcolemma. In turn, CD36 recycling was recently found to be regulated by instantaneous changes in activity of vacuolar‐type H+‐ATPase (v‐ATPase) in the endosomes, as controlled by rapid assembly and disassembly of V0 and V1 subunits of v‐ATPase.

Plasma membrane CD 36 FABP Fatty acid 1 2 6 7 4 5 3 Cytoplasm Interstitium albumin

Abstract: Purpose of review Transmembrane glycoprotein cluster of differentiation 36 (CD36) is a scavenger receptor class B protein (SR-B2) that serves various functions in lipid metabolism and signaling, in particular facilitating the cellular uptake of long-chain fatty acids. Recent studies have disclosed CD36 to play a prominent regulatory role in cellular fatty acid metabolism in both health and disease.