Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear.1–3 Insulin resistance in skeletal muscle stems from excess accumulation of lipid species4, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

The DNA base excision repair pathway is responsible for the repair of DNA damage caused by oxidation/alkylation and protects cells against the effects of endogenous and exogenous agents. Removal of the damaged base by creates a baseless (AP) site. AP endonuclease1 (Ape1) acts upon this site to continue the BER pathway repair. Failure to repair baseless sites leads to DNA strand breaks and cytotoxicity. In addition to Ape1's repair role, it also functions as a major redox signaling factor to reduce and activate transcription factors such as AP1, p53, HIF-1α and others which control the expression of genes important for cell survival and cancer promotion and progression. Thus the Ape1 protein interacts with proteins involved in DNA repair, growth signaling pathways and pathways involved in tumor promotion and progression. While knockdown studies using siRNA have been informative in studying the role of Ape1 in both normal and cancer cells, knocking down Ape1 does not reveal the individual role of Ape1's redox or repair functions. The identification of small molecule inhibitors of specific Ape1 functions is critical for mechanistic studies and translational applications. Here we discuss small molecule inhibition of Ape1 redox and its effect on both cancer and endothelial cells.

Abstract:The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last 10 years have seen a resurgent interest in cardiac intermediary metabolism and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-␥ coactivator ( Key Words: PGC-1 Ⅲ metabolism Ⅲ heart failure Ⅲ mitochondria T he heart consumes tremendous amounts of energy. ATP consumption, per weight of tissue, is the highest in the body. Energy reserves in the heart are relatively limited, and a heart starved of its fuel and oxygen supply can only beat 20 to 40 times (a few seconds) before succumbing to energy deficiency. Despite this narrow window, the healthy heart will contract billions of times in the average human life. The dynamic range of cardiac activity is large, both acutely (exercise) and chronically (development, especially postnatal). Bioenergetic programs in the heart must therefore be tightly regulated.ATP is the currency of energy in the cell. Oxidative consumption of fuels in mitochondria is by far the most efficient means of generating ATP, yielding Ͼ30 ATP per molecule of glucose, compared to a net 2 ATP via anaerobic glycolysis and lactate production. It is not surprising then that the heart is highly aerobic and sustains Ͼ95% of its ATP output via oxidative breakdown of fuels. Oxidative phosphorylation of ATP occurs strictly in mitochondria, and the heart therefore maintains a high mitochondrial content. The energetic requirements of the heart increase dramatically at birth, and mitochondrial density accordingly increases sharply during the perinatal period. 1-3 Mitochondrial mass makes up fully one-third of the adult heart.The PPAR-␥ coactivator (PGC)-1 transcriptional coactivators have recently emerged as powerful regulators of mitochondrial biology in the heart, by broadly regulating gene expression from both nuclear and mitochondrial genomes. The expression of PGC-1␣ is repressed in numerous models of heart failure, and this has been implicated as an important contributor to the maladaptive energetic profile of failing hearts. This review focuses on the PGC-1s and their role in cardiac biology. PGC-1 CoactivatorsCoactivators are proteins that bind to nuclear receptors or other transcription factors and increase their ability to stimulate transcriptional activity. Most transcription factors likely require coactivators. A subset of coactivators are highly regulated and transduce extra-and intracellular cues to Original

Summary Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.