Cardiac lipotoxicity: molecular pathways and therapeutic implications

Abstract

Diabetes and obesity are both associated with lipotoxic cardiomyopathy exclusive of coronary artery disease and hypertension. Lipotoxicities have become a public health concern and are responsible for a significant portion of clinical cardiac disease. These abnormalities may be the result of a toxic metabolic shift to more fatty acid and less glucose oxidation with concomitant accumulation of toxic lipids. Lipids can directly alter cellular structures and activate downstream pathways leading to toxicity. Recent data have implicated fatty acids and fatty acyl coenzyme A, diacylglycerol, and ceramide in cellular lipotoxicity, which may be caused by apoptosis, defective insulin signaling, endoplasmic reticulum stress, activation of protein kinase C, MAPK activation, or modulation of PPARs.

Figure 1

Proteins and transcriptional factors that modulate fatty acid oxidation

Figure 2. Lipid delivery to the cardiomyocyte

Fatty acids derived from triglyceride-rich lipoproteins, chylomicrons, and VLDL are hydrolyzed by lipoprotein lipase. Lipoprotein-derived fatty acids or albumin-bound free fatty acids are internalized by the cells via membrane receptors such as CD36 or other transporters, or via non-receptor diffusion through the membrane, known as “flip-flop”. Internalization of whole lipoproteins or lipoprotein remnants via lipoprotein receptors is also possible. Upon release into cardiomyocytes fatty acids are converted to fatty acyl-CoAs and can then gradually incorporated to a glycerol backbone forming mono-, di- and tri-acyl-glycerols (triglycerides). Fatty acyl-CoAs can be released via triglyceride lipolysis that is mediated by ATGL, HSL and MGL and with the contribution of Cpt-1 they enter mitochondria for β-oxidation and production of ATP.

Figure 3. Metabolic pathways triggered by palmitic acid leading to apoptosis and cardiomyopathy

Several mechanisms may account for the toxic effects of saturated fatty acids: 1. Palmitic Acid is used by Serine Palmitoyl Transferase to generate cytoplasmic ceramide, which activates JNK1/2 that interacts with Bax in the mitochondrial membrane and results in the release of cytochrome C due to reduction of cardiolipin (ceramide-dependent mechanism). 2. Palmitic acid can inhibit AMPK, which increases malonyl-CoA levels, inhibits CPT-1, and causes accumulation of fatty acids and lipotoxicity. 3. Palmitic acid contributes to the increase of DAG that induces the upregulation of PKC. PKC inhibits the insulin-signaling pathway by blocking IRS-1. 4. The insulin-signaling pathway can be inhibited by ceramide-mediated increased PP2A, which dephosphorylates (inactivates) the anti-apoptotic PKB/Akt; inhibition of PKB/Akt may induce apoptosis. Dephosphorylated Akt reduces AMPK activity that can lead to lipotoxicity (see above). 5. Palmitic acid may be incorporated into phospholipid and TG species in microsomal membranes, resulting in compromised ER membrane integrity and redistribution of protein-folding chaperones to the cytosol (ER stress). 6. Esterification of palmitate can also cause ER fission directly. Intensive ER stress may result in apoptosis.