Establishing Foundation Archives: A Reader and Guide to First Steps

This publication is an anthology of papers presented at a conference held at the Rockefeller Archive Center in January 1990, and sponsored by the Council on Foundations. This collaboration of the Archive Center and the Council provided a rare opponunity for foundations to learn both why preserving documents is imponant and how several foundations have approached finding a repository or setting up and managing an archives. Participants in the conference had the added privilege of conferring with experts and seeing an operating archive as they toured the Rockefeller Archive Center.Foundations are institutions that are shaping private initiatives for the public good, so documenting this aspect of American society falls uniquely under the stewardship of the organizations themselves. Foundation documents often provide the only surviving records of the important contributions of nonprofits and foundations to civic life. These records will help to inform future judgments and ensure that the history of the field is not lost. The publication of this volume was intended to make the information shared at the conference more widely available and to provide an entry point and a primer for foundations as they begin their records and archives journey

Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules1. LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation2,3,4,5,6. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1–containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1–selective activators and promote LCFA oxidation

Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity

Metformin is the mainstay therapy for type 2 diabetes (T2D) and many patients also take salicylate-based drugs [i.e., aspirin (ASA)] for cardioprotection. Metformin and salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) and salicylate interacting directly at the AMPK β1 drug-binding site. AMPK activation by both drugs results in phosphorylation of ACC (acetyl-CoA carboxylase; P-ACC) and inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme controlling fatty acid synthesis (lipogenesis). We find doses of metformin and salicylate used clinically synergistically activate AMPK in vitro and in vivo, resulting in reduced liver lipogenesis, lower liver lipid levels and improved insulin sensitivity in mice. Synergism occurs in cell-free assays and is specific for the AMPK β1 subunit. These effects are also observed in primary human hepatocytes and patients with dysglycaemia exhibit additional improvements in a marker of insulin resistance (proinsulin) when treated with ASA and metformin compared with either drug alone. These data indicate that metformin–salicylate combination therapy may be efficacious for the treatment of non-alcoholic fatty liver disease (NAFLD) and T2D