Putative Role of Protein Palmitoylation in Cardiac Lipid-Induced Insulin Resistance

Abstract

In the heart, inhibition of the insulin cascade following lipid overload is strongly associated with contractile dysfunction. The translocation of fatty acid transporter CD36 (SR-B2) from intracellular stores to the cell surface is a hallmark event in the lipid-overloaded heart, feeding forward to intracellular lipid accumulation. Yet, the molecular mechanisms by which intracellularly arrived lipids induce insulin resistance is ill-understood. Bioactive lipid metabolites (diacyl-glycerols, ceramides) are contributing factors but fail to correlate with the degree of cardiac insulin resistance in diabetic humans. This leaves room for other lipid-induced mechanisms involved in lipid-induced insulin resistance, including protein palmitoylation. Protein palmitoylation encompasses the reversible covalent attachment of palmitate moieties to cysteine residues and is governed by protein acyl-transferases and thioesterases. The function of palmitoylation is to provide proteins with proper spatiotemporal localization, thereby securing the correct unwinding of signaling pathways. In this review, we provide examples of palmitoylations of individual signaling proteins to discuss the emerging role of protein palmitoylation as a modulator of the insulin signaling cascade. Second, we speculate how protein hyper-palmitoylations (including that of CD36), as they occur during lipid oversupply, may lead to insulin resistance. Finally, we conclude that the protein palmitoylation machinery may offer novel targets to fight lipid-induced cardiomyopathy.

Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies

“…The impact of other zDHHC5 PTMs on its activity will be important to consider in future investigations, as phosphorylation has been observed to inactivate zDHHC5 ( Hao et al, 2020 ; Schianchi et al, 2020 ), while O-GlycNAcylation of zDHHC5 enhanced PLM association and palmitoylation ( Plain et al, 2020 ; Schianchi et al, 2020 ). In line with our observations from hypertrophic tissue, but in contrast to the ischaemic human HF results, Miles et al (2021) report significantly increased levels of zDHHC5 in human HF.…”

zDHHC5 expression is increased in cardiac hypertrophy and reduced in heart failure but this does not correlate with changes in substrate palmitoylation

“…Additionally, other PTMs of zDHHC5 will be important to consider in future investigations, as phosphorylation has been observed to inactivate zDHHC5 (Hao et al ., 2020; Schianchi et al ., 2020), while O-GlycNAcylation of DHHC5 enhanced PLM association and palmitoylation (Plain et al ., 2020; Schianchi et al ., 2020). In line with hypertrophy data, but in contrast to the ischaemic human HF results, Miles et al .…”

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

“…These aspects include the trafficking machinery involved in the translocation of CD36 from endosomes to the plasma membrane and vice versa , the putative activation of CD36 after its arrival at the plasma membrane and required for optimal function [ 56 ], the presumable interaction with membrane lipids and with other membrane proteins (such as caveolin and FABP pm ) [ 57 , 58 ], and the significance of posttranslational modification of CD36 for its functioning [ 59 , 60 ▪ ]. With respect to the latter, CD36 requires palmitoylation for its proper insertion into the membrane but its hyper-palmitoylation may occur during lipid oversupply and then will contribute to lipid accumulation and the development of insulin resistance [ 9 ▪▪ , 61 ]. Such additional insights, together with the availability of the structure and membrane topology of CD36 [ 62 ] will accelerate the design of small-molecule compounds to be used as pharmacological agents to specifically influence CD36 functioning [ 63 ▪ ].…”