The Regulation of Insulin-Stimulated Cardiac Glucose Transport via Protein Acetylation

Abstract

Cellular catabolism is the cell capacity to generate energy from various substrates to sustain its function. To optimize this energy production, cells are able to switch between various metabolic pathways in accordance to substrate availability via a modulation of several regulatory enzymes. This metabolic flexibility is essential for the healthy heart, an organ requiring large quantities of ATP to sustain its contractile function. In type 2 diabetes, excess of non-glucidic nutrients such as fatty acids, branched-chain amino-acids, or ketones bodies, induces cardiac metabolic inflexibility. It is characterized by a preferential use of these alternative substrates to the detriment of glucose, this participating in cardiomyocytes dysfunction and development of diabetic cardiomyopathy. Identification of the molecular mechanisms leading to this metabolic inflexibility have been scrutinized during last decades. In 1963, Randle demonstrated that accumulation of some metabolites from fatty acid metabolism are able to allosterically inhibit regulatory steps of glucose metabolism leading to a preferential use of fatty acids by the heart. Nevertheless, this model does not fully recapitulate observations made in diabetic patients, calling for a more complex model. A new piece of the puzzle emerges from recent evidences gathered from different laboratories showing that metabolism of the non-glucidic substrates induces an increase in acetylation levels of proteins which is concomitant to the perturbation of glucose transport. The purpose of the present review is to gather, in a synthetic model, the different evidences that demonstrate the role of acetylation in the inhibition of the insulin-stimulated glucose uptake in cardiac muscle.

Cardiac metabolism as a driver and therapeutic target of myocardial infarction

“…19 In line, we recently showed that increased protein acetylation by metabolic over-fuelling dramatically reduced both insulin-and AMPK-mediated glucose uptake in cardiomyocytes, presuming the importance of reducing protein acetylation for promoting glucose metabolism during IRI. 110,111 Overall, while promoting deacetylation, for example by targeting SIRT1 activation, is an attractive avenue for cardioprotection, considerable effort is required for the development of specific drugs to achieve this end.…”

Targeting the glucagon receptor improves cardiac function and enhances insulin sensitivity following a myocardial infarction

“…Acetylation is a post-translational modification that can modify the activity glucose and fatty acid metabolism regulatory enzymes [47, 48]. Overall protein acetylation in the MI heart was not changed compared to sham group (Fig.…”

Understanding the distinct subcellular trafficking of CD36 and GLUT4 during the development of myocardial insulin resistance

“…Increased fatty acid oxidation leads to increased levels of acetyl-CoA and of protein acetylation. On its turn, protein acetylation inhibits insulin signaling at multiple levels as well as insulin-stimulated GLUT4 translocation via unknown mechanisms [26]. The fatty acid metabolites are mostly made up of triacylglycerols stored in lipid droplets.…”