!-lipoic Acid in Liver Metabolism and Disease

R-!-Lipoic acid is found naturally occurring as a prosthetic group in !-keto acid dehydrogenase complexes of the mitochondria, and as such plays a fundamental role in metabolism. Although this has been known for decades, only recently has free supplemented !-lipoic acid been found to affect cellular metabolic processes in vitro, as it has the ability to alter the redox status of cells and interact with thiols and other antioxidants. Therefore, it appears that this compound has important therapeutic potential in conditions where oxidative stress is involved. Early case studies with !-lipoic acid were performed with little knowledge of the action of !-lipoic acid at a cellular level, but with the rationale that because the naturally occurring protein bound form of !-lipoic acid has a pivotal role in metabolism, that supplementation may have some beneficial effect. Such studies sought to evaluate the effect of supplemented !-lipoic acid, using low doses, on lipid or carbohydrate metabolism, but little or no effect was observed. A common response in these trials was an increase in glucose uptake, but increased plasma levels of pyruvate and lactate were also observed, suggesting that an inhibitory effect on the pyruvate dehydrogenase complex was occurring. During the same period, !-lipoic acid was also used as a therapeutic agent in a number of conditions relating to liver disease, including alcohol-induced damage, mushroom poisoning, metal intoxification, and CCl4 poisoning. !-Lipoic acid supplementation was successful in the treatment for these conditions in many cases. Experimental studies and clinical trials in the last 5 years using high doses of !-lipoic acid (600 mg in humans) have provided new and consistent evidence for the therapeutic role of antioxidant !-lipoic acid in the treatment of insulin resistance and diabetic polyneuropathy. This new insight should encourage clinicians to use !-lipoic acid in diseases affecting liver in which oxidative stress is involved. © 1998 Elsevier Science Inc. Keywords—!-Lipoic acid, Thioctic acid, Oxidative stress, Free radicals, Liver, Disease, Primary biliary cirrhosis Address correspondence to: Lester Packer, Membranes Bioenergetics Group, Department of Molecular and Cell Biology, 251 Life Sciences Addition, University of California, Berkeley 94720-3200. L.M. is on leave from the Department of Biochemical Sciences ‘‘A. Rossi Fanelli’’ and CNR Center of Molecular Biology, University of Rome ‘‘La Sapienza’’ Piazzale Aldo Moro 5, 00185 Rome, Italy. B.H.R. is on leave from Institut National de Recherche et de Sécurité, Avenue de Bourgogne, 54500 Vandoeuvre, France. Dr. Lester Packer is a professor in the Department of Molecular and Cell Biology at the University of California at Berkeley. He received a Ph.D. in Microbiology and Biochemistry from Yale University in 1956. At Berkeley he has been Professor of Physiology since 1961; Director of the Membrane Bioenergetics Group at the University of California at Berkeley, and a Senior Scientist at the Lawrence Berkeley Laboratory since 1972. His research in the area of biological oxidation and bioenergetics has emphasized studies on the role of oxidants and antioxidants in biological systems. Recent work concerns the prevention of oxidatively-induced injury in biological systems by antioxidants and how networking antioxidants such as vitamin E, C, and lipoic acid affect gene expression and cell regulation. Dr. Bertrand Rihn is Head of the Laboratory of Experimental Carcinogenesis at the Institut National de Recherche et de Sécurité, Vandoeuvre, and Head of the PCR Laboratory, Centre Hospitalo-Universitaire Régional de Brabois, Vandoeuvre, France. He obtained an M.D. at the Université Louis Pasteur (Strasbourg) in 1982, and in 1991 received his Ph.D. His current research interests are in the development of nonradioactive methods for molecular biology, the development of new tools for in vivo experimental carcinogenesis, and the evaluation of carcinogenicity of chemical compounds. Dr. Juanita Bustamante is a researcher at the Catedra de Fisicoquimica Facultad de Farmacia y Bioquimica, University of Buenos Aires, Argentina. She obtained her Ph.D. in Chemical Sciences at the University of Buenos Aires in 1991. Her research interests are in the role of antioxidants and oxidants in apoptosis. Dr. John K. Lodge is a researcher in the Department of Molecular and Cell Biology at the University of California at Berkeley. He obtained his Ph.D. in Biological Chemistry at the University of London in 1993. His current research interests are in oxidative stress. Dr. Lucia Marcocci is a researcher in the Dipartimento di Scienze Biochimiche ‘‘A. Rossi Fanelli,’’ at the Universita’ di Roma ‘‘La Sapienza.’’ She received a Ph.D. in Biochemistry at the Universita’ di Roma ‘‘La Sapienza’’ in 1991. Her research interests are in oxidative stress. Free Radical Biology & Medicine, Vol. 24, No. 6, pp. 1023–1039, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/98 $19.00 ! .00 PII S0891-5849(97)00371-7