Polyunsaturated fatty acid deficiency reverses effects of alcohol on mitochondrial energy metabolism Marie-Astrid Piquet 1,2, * , Michel Roulet 3 , Ve ´ronique Nogueira 2 , Ce ´line Filippi 2 , Brigitte Sibille 2 , Isabelle Hourmand-Ollivier 1 , Marianne Pilet 3 , Vincent Rouleau 4 , Xavier M. Leverve 2 1 De ´partement d’He ´patologie et Nutrition, CHU, F-14033 Caen cedex, France 2 Laboratoire de Bioe ´nerge ´tique Fondamentale et Applique ´e, UJF, F-38041 Grenoble, France 3 Laboratoire de Nutrition Clinique, CHUV, CH-1011 Lausanne, Switzerland 4 Laboratoire d’Anatomo-Pathologie, CHU, F-14033 Caen cedex, France Background/Aims: Polyunsaturated fatty acids (PUFA) deficiency is common in patients with alcoholic liver disease. The suitability of reversing such deficiency remains controversial. The aim was to investigate the role played by PUFA deficiency in the occurrence of alcohol-related mitochondrial dysfunction. Methods: Wistar rats were fed either a control diet with or without alcohol (control and ethanol groups) or a PUFA deficient diet with or without alcohol (PUFA deficient and PUFA deficientCethanol groups). After 6 weeks, liver mitochondria were isolated for energy studies and fatty acid analysis. Results: Mitochondria from ethanol fed rats showed a dramatic decrease in oxygen consumption rates and in cytochrome oxidase activity. PUFA deficiency showed an opposite picture. PUFA deficientCethanol group roughly reach control values, regarding cytochrome oxidase activity and respiratory rates. The relationship between ATP synthesis and respiratory rate was shifted to the left in ethanol group and to the right in PUFA-deficient group. The plots of control and PUFA deficientCethanol groups were overlapping. Phospholipid arachidonic over linoleic ratio closely correlated to cytochrome oxidase and oxygen uptake. Conclusions: PUFA deficiency reverses alcohol-related mitochondrial dysfunction via an increase in phospholipid arachidonic over linoleic ratio, which raises cytochrome oxidase activity. Such deficiency may be an adaptive mechanism. q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Polyunsaturated fatty acids; Alcohol; Mitochondria 1. Introduction Polyunsaturated fatty acids (PUFA) deficiency is a common finding in patients with alcoholic liver disease [1–3]. Its role in pathogenesis of liver disease is unclear and the suitability of reversing such PUFA deficiency remains controversial [4,5]. On the one hand, PUFA deficiency may have deleterious functional repercussions, because PUFA enclose important biological functions such as cell membrane components, which regulate membrane fluidity and protein activities, and as pre- cursors of biologically active compounds. Such detri- mental effect is suggested by the finding that PUFA deficiency is an independent predictive factor of mortality in patients with alcoholic cirrhosis [1]. On the other hand, PUFA deficiency could be viewed as an adaptive phenomenon having beneficial effects. Experi- mental studies reported that, in alcohol fed rats, a PUFA enriched diet leads to more severe liver injury than a diet enriched in saturated fatty acids [6,7]. An explicative hypothesis proposed is that PUFA increase lipid peroxi- dation. Actually, unsaturated fat acts as a preferential substrate for peroxidation and induces cytochrome 0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2004.07.002 Journal of Hepatology 41 (2004) 721–729 www.elsevier.com/locate/jhep Received 21 February 2004; received in revised form 26 June 2004; accepted 2 July 2004; available online 31 July 2004 * Corresponding author. Address: Department of d’He ´patogastroente ´r- ologie et Nutrition, CHU, F-14033 CAEN Cedex, France. Tel.: C33-2-31- 06-45-14; fax: C33-2-31-06-45-45. E-mail address: piquet-ma@chu-caen.fr (M.-A. Piquet).