Key result
NMN prevents CD36-mediated lipid accumulation and cardiac dysfunction by maintaining v-ATPase activity and endosomal acidification.
Why the study?
Strategies inducing v-ATPase reassembly to achieve CD36 reinternalization may correct maladaptive alterations in lipid-induced cardiomyopathy.
NMN supplementation ameliorates lipid-induced cardiomyopathy in animal models by preserving v-ATPase assembly and repressing the CD36-TLR4 axis.
Should not change clinical practice; hypothesis-generating for NMN in metabolic cardiomyopathy.
BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H + -ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD + (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [ 3 H]chloroquine (endosomal pH), and [ 14 C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V 1 G1/V 0 d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.
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Wang et al. (2024) studied Lipid-induced cardiomyopathy. Nicotinamide mononucleotide (NMN) vs. High-fat diet alone / lysine/leucine/arginine cocktail was evaluated on Endosomal acidification, CD36-mediated lipid accumulation, inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. NMN preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity, preventing CD36-mediated lipid accumulation, inflammation, fibrosis, and cardiac dysfunction.
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