Preface [ Hot Topic: The Physiological and Pharmacological Regulation of Lipid Metabolism (Guest Editor: Dr. Michael E. Pape)]

Years ago in graduate school I remember being told by my mentor to do a Folch extraction. As a young researcher I knew nothing of Folch or much about lipids for that matter. However, recently it occurred to me that perhaps Folch anticipated the recent genomics field and its related offspring-proteomics, metabolomics, and so on. In light of the recent explosion of “omics” of every variety and flavor, it would not be unreasonable to call Jordi Folch the father of “lipomics”. While focusing on brain biochemistry, his fundamental philosophy was that “everything must be accounted for” (1). This ultimately led to the 1957 paper entitled “A simple method for the isolation and purification of total lipids from animal tissues”; one of the most cited papers in all of life science literature (2). The paper describes the quantitative isolation of lipids from biological sources. At that time, researchers in the lipid field were not only focusing on the structure and mass of various lipid molecules, but also their biosynthesis. Konrad Bloch and Feodor Lynen were working out the biosynthetic details of cholesterol and fatty acid synthesis (3). In more recent times, research efforts have extended lipid biochemistry knowledge by focusing on regulatory mechanisms that control the biosynthesis and degradation of lipids. Short-term regulation involving changes in enzyme specific activity can be mediated by allosteric and covalent modification mechanisms while long-term regulation involving changes in protein levels can be mediated in part by altered gene expression. That abnormal regulation of lipid metabolism is associated with human diseases is undisputed; heart disease, obesity, dyslipidemia, and diabetes are only a few disorders that display various abnormalities in lipid metabolism. To treat those disorders, researchers continue to draw on past, basic metabolism work to guide drug discovery approaches and develop new therapeutics. Indeed, it was the intention of the contributors and me to put together a thematic issue of Current Medicinal Chemistry-Immunology, Endocrine, and Metabolic Agents that would integrate knowledge of short- and long-term regulatory mechanisms of key enzymes involved in lipid metabolism with practical aspects of discovering new drugs to treat diseases associated with lipid disorders. This issue represents that aim. This series of reviews is entitled “The Physiological and Pharmacological Regulation of Lipid Metabolism”. The first two articles provide up to date reviews on the regulatory mechanisms in the synthesis of acetyl-CoA, a central building block in lipid biosynthesis. Takahiro Fujino and co-workers nicely review the present state of knowledge on acetyl-CoA synthetases in an article entitled “Sources of acetyl-CoA: acetyl-CoA synthetase 1 and 2”. Next, Pieter Groot, Nigel Pearce, and Andrew Gribble describe an alternative pathway to generate acetyl-CoA, namely, through the enzyme ATP-citrate lyase. Their article is entitled, “ATP-citrate lyase: a potential target for hypolipidemic intervention.” These authors have weaved a wonderful story that integrates basic knowledge of lipid metabolism and short-term control mechanisms with a robust drug discovery approach to identify synthetic inhibitors of this enzyme. Once acetyl-CoA is formed it is can be utilized to synthesize cholesterol or fatty acids which involves HMG-CoA reductase and acetyl-CoA carboxylase, respectively; both enzymes are covered in this issue. Gene Ness provides an excellent overview of HMG-CoA reductase regulation with an emphasis on longterm control mechanisms elicited by hormones and the statin class of drugs in an article entitled, “Physiological and pharmacological regulation of hepatic 3-hydroxy-3-methylglutaryl Coenzyme A reductase”. With respect to acetyl-CoA carboxylase, Grover Waldrop and Jaqueline Stephens provide a review entitled “Targeting acetyl-CoA carboxylase for anti-obesity therapy”. Their novel approach to designing inhibitors of this enzyme provides an excellent example of utilizing knowledge of enzyme structure-function and substrates/products to synthesize “anti-metabolites”. The final article by Kathleen Knights is a thorough and fluid treatment of the fatty-acid CoA ligase family of enzymes. This family is central not only to lipid metabolism in general but particularly in the handling of xenobiotics that alter lipid metabolism. Indeed, the ligases catalyze the formation of xenobiotic acyl-CoA thioesters which actually may be mediators of some drug effects. The title of this review is “Long-chain fatty acid CoA ligases: the key to fatty acid activation, formation of xenobiotic acyl-CoA thioesters and lipophilic xenobiotic conjugates.” The contributors and I hope these series of articles spur novel ideas and approaches that may one day lead to new therapeutics to treat lipid and associated disorders. [1] Lees, M.B and Pope, A. Jordi Folch-Pi, In Biographical Memoirs, 2001, 79, pg 3-24. The National Acadamy Press, Washington, D.C. [2] Folch, J., Lees, M. and Stanley, G.H.S. J. Biol. Chem., 1957, 226, 497-509. [3] Kennedy, E.P. J. Biol. Chem., 2001, 276, 42619-42631.