Lipotoxicity in diabetic cardiomyopathy

Diabetes is growing at an alarming rate in North America. The biggest killer of patients with diabetes is heart disease. Indeed, diabetes is a major risk factor for both coronary artery disease and hypertension. However, patients with diabetes are also at risk for developing diabetic cardiomyopathy (DCM), which is characterized as heart disease in the absence of atherosclerosis and hypertension. The exact causes of this diabetic heart disease has not been completely elucidated but abnormal lipid metabolism has emerged as a key contributing factor. Interestingly, a common characteristic of DCM is the accumulation of intra cellular lipids otherwise known as cardiac steatosis. Cardiac steatosis is likely caused by a mismatch between lipid uptake and lipid clearance from the cells. As such, we focused on elucidating the mechanisms of lipotoxicity in the context of diabetic cardiomyopathy. To this end, we investigated the role of lipid metabolism on key pathways related to diabetic cardiomyopathy including Endoplasmic Reticulum (ER) stress, Peroxisome proliferator-activated receptors (PPARs) activity, inflammation, and mitochondrial dysfunction with a specific focus on fatty acid oxidation. We characterized lipid induced ER stress and apoptosis in vitro, using primary neonatal cardiomyocytes. We were able to confirm that palmitate, a lipotoxic fatty acid, induces ER stress and cell death in primary cardiomyocytes. We also demonstrated that palmitate mediated lipotoxicity is associated with a significant degree of inflammation which may be due to down-regulation of PPAR receptors. Cardiac steatosis and lipotoxicity can alter metabolic signaling pathways leading to mitochondrial dysfunction. We discovered that palmitate toxicity is associated with an impairment of complete fatty acid oxidation (FAO). Specifically, palmitate impairs β-oxidation and citric acid cycle simultaneously with no effect on Cpt1b activity, the rate limiting step in FAO. Interestingly enhancing FAO attenuated the toxic effects of palmitate while inhibiting FAO caused oleate, which is normally non-toxic, to induce cell death. These results suggest that enhancing FAO might have some clinical utility as a therapeutic target for the treatment of diabetic cardiomyopathy. As such, we have investigated whether impaired fatty acid oxidation might contribute to DCM pathology in vivo. Previous studies have shown that FAO is actually increased in diabetic mice. However, diabetic mice also exhibit elevated fatty acid uptake which could significantly contribute to the elevated FAO rates in these hearts. Therefore, we aimed to assess FAO rates directly from isolated mitochondria instead of whole hearts to exclude the potentially confounding factor of enhanced fatty acid uptake. We found that older (chronic) diabetic mice exhibited impaired fatty acid oxidation rates and this was associated with ER stress and impaired cardiac function. In contrast, acutely diabetic mice had normal cardiac functions which was associated with normal FAO rates. Taken together, these studies have furthered our understanding of lipotoxic mechanisms in the context of diabetic cardiomyopathy and they accentuated the importance of ER stress, inflammation, and impaired mitochondrial function as key factors promoting lipotoxicity in diabetic cardiomyopathy.

Keyphrases: cardiomyocytes, Fatty acids, Fatty acids, Lipotoxicity, fatty acids oxidation, Endoplasmic reticulum stress, type 2 diabetes, steatosis, cardiomyocytes