Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.

Apolipoprotein AI (apoAI) is a lipid-binding protein that participates in the transport of cholesterol and other lipids in the plasma. A complementary DNA clone for a protein that bound to regulatory elements of the apoAI gene was isolated. This protein, designated apoAI regulatory protein-1 (ARP-1), is a novel member of the steroid hormone receptor superfamily. ARP-1 bound to DNA as a dimer, and its dimerization domain was localized to the COOH-terminal region. ARP-1 also bound to a thyroid hormone-responsive element and to regulatory regions of the apoB, apoCIII, insulin, and ovalbumin genes. In cotransfection experiments, ARP-1 downregulated the apoAI gene. The involvement of ARP-1 in the regulation of apoAI gene expression suggests that it may participate in lipid metabolism and cholesterol homeostasis.

Rationale Cardiac progenitor cells are an attractive cell type for tissue regeneration but their mechanism for myocardial remodeling is still unclear. Objective This investigation determines how chronological age influences the phenotypic characteristics and the secretome of human cardiac progenitor cells (CPCs), as well as their potential to recover injured myocardium. Methods and Results Adult (aCPCs) and neonatal (nCPCs) cells were derived from patients more than 40 years or less than one month of age, respectively, and their functional potential was determined in a rodent myocardial infarction (MI) model. A more robust in vitro proliferative capacity of nCPCs, compared to aCPCs, correlated with significantly greater myocardial recovery mediated by nCPCs in vivo. Strikingly, a single injection of nCPC-derived total conditioned media (nTCM) was significantly more effective than nCPCs, aCPC-derived TCM (aTCM), or nCPC-derived exosomes in recovering cardiac function, stimulating neovascularization, and promoting myocardial remodeling. High resolution accurate mass spectrometry (HRAMS) with reverse phase liquid chromatography fractionation and mass spectrometry (LC-MS/MS) was employed to identify proteins in the secretome of aCPCs and nCPCs, and literature-based networking software identified specific pathways affected by the secretome of CPCs in the setting of MI. Examining the TCM, we quantified changes in the expression pattern of 804 proteins in nTCM and 513 proteins in aTCM. Literature-based proteomic network analysis identified that 46 and 6 canonical signaling pathways were significantly targeted by nTCM and aTCM, respectively. One leading candidate pathway is heat shock factor-1 (HSF-1), potentially affecting 8 identified pathways for nTCM but none for aTCM. To validate this prediction, we demonstrated that modulation of HSF-1 by knockdown in nCPCs or overexpression in aCPCs significantly altered the quality of their secretome. Conclusions In conclusion, a deep proteomic analysis revealed both detailed and global mechanisms underlying the chronological age-based differences in the ability of CPCs to promote myocardial recovery via the components of their secretome.

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