MicroRNAs 33, 122, and 208: a potential novel targets in the treatment of obesity,diabetes, and heart-related diseases

Despite decades of research, obesity and diabetes remain major health problems in the USA and worldwide. Among the many complications associated with diabetes is an increased risk of cardiovascular diseases, including myocardial infarction and heart failure. Recently, microRNAs have emerged as important players in heart disease and energy regulation. However, little work has investigated the role of microRNAs in cardiac energy regulation. Both human and animal studies have reported a significant increase in circulating free fatty acids and triacylglycerol, increased cardiac reliance on fatty acid oxidation, and subsequent decrease in glucose oxidation which all contributes to insulin resistance and lipotoxicity seen in obesity and diabetes. Importantly, MED13 was initially identified as a negative regulator of lipid accumulation in Drosophilia. Various metabolic genes were downregulated in MED13 transgenic heart, including sterol regulatory element-binding protein. Moreover, miR-33 and miR-122 have recently revealed as key regulators of lipid metabolism. In this review, we will focus on the role of microRNAs in regulation of cardiac and total body energy metabolism. We will also discuss the pharmacological and non-pharmacological interventions that target microRNAs for the treatment of obesity and diabetes.     

Role of AMP-activated protein kinase in healthy and diseased hearts

The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed.     

Krüppel-like transcription factor 11 (KLF11) overexpression inhibits cardiac hypertrophy and fibrosis in mice

The Krüppel-like factors (KLFs) belong to a subclass of Cys2/His2 zinc-finger DNA-binding proteins. The KLF family member KLF11 is originally identified as a transforming growth factor β (TGF-β)-inducible gene and is one of the most studied in this family. KLF11 is expressed ubiquitously and participates in diabetes and regulates hepatic lipid metabolism. However, the role of KLF11 in cardiovascular system is largely unknown. Here in this study, we reported that KLF11 expression is down-regulated in failing human hearts and hypertrophic murine hearts. To evaluate the roles of KLF11 in cardiac hypertrophy, we generated cardiac-specific KLF11 transgenic mice. KLF11 transgenic mice do not show any difference from their littermates at baseline. However, cardiac-specific KLF11 overexpression protects mice from TAC-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observe lower expression of hypertrophic fetal genes in TAC-challenged KLF11 transgenic mice compared with WT mice. In addition, KLF11 reduces cardiac fibrosis in mice underwent hypertrophy. The expression of fibrosis markers are also down-regulated when KLF11 is overexpressed in TAC-challenged mice. Taken together, our findings identify a novel anti-hypertrophic and anti-fibrotic role of KLF11, and KLF11 activator may serve as candidate drug for heart failure patients.     

Metabolic reprogramming of the heart through stearoyl-CoA desaturase

Stearoyl-CoA desaturase (SCD), a central enzyme in lipid metabolism that synthesizes monounsaturated fatty acids, has been linked to tissue metabolism and body adiposity regulation. Recent studies showed that SCD has the ability to reprogram cardiac metabolism, thereby regulating heart function. In the heart, the lack of SCD1 enhances glucose transport and metabolism at the expense of fatty acid (FA) uptake and oxidation. The metabolic changes associated with SCD1 deficiency protect cardiac myocytes against both necrotic and apoptotic cell death and improve heart function. Furthermore, SCD4, a heart-specific isoform of SCD, is specifically repressed by leptin and the lack of SCD1 function in leptin-deficient ob/ob mice results in a decrease in the accumulation of neutral lipids and ceramide and improves the systolic and diastolic function of a failing heart. Large-population human studies showed that the plasma SCD desaturation index is positively associated with heart rate, and cardiometabolic risk factors are modulated by genetic variations in SCD1. The current findings indicate that SCD may be used to reprogram myocardial metabolism to improve cardiac function. Here, we review recent advances in understanding the role of SCD in the control of heart metabolism and its involvement in the pathogenesis of lipotoxic cardiomyopathies.