Biochem. J. (2005) 385
(787–794) (Printed in Great Britain)
Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids
Catherine LE JOSSIC-CORCOS*1, Céline GONTHIER*, Isabelle ZAGHINI*, Emmanuelle LOGETTE†, Ishaiahu SHECHTER‡ and Paulette BOURNOT*
*Laboratoire de Biologie Moléculaire et Cellulaire (GDR CNRS no. 2583), Université de Bourgogne, 21000 Dijon, France, †Inserm U517, Faculté de Médecine, 7 Bd Jeanne d'Arc, 21000 Dijon, France, and ‡Department of Surgery, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, U.S.A.
Dietary vegetable oils and fish oils rich in PUFA (polyunsaturated fatty acids) exert hypocholesterolaemic and hypotriglyceridaemic effects in rodents. The plasma cholesterol-lowering properties of PUFA are due partly to a diminution of cholesterol synthesis and of the activity of the rate-limiting enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase). To better understand the mechanisms involved, we examined how tuna fish oil and individual n-3 and n-6 PUFA affect the expression of hepatic FPP synthase (farnesyl diphosphate synthase), a SREBP (sterol regulatory element-binding protein) target enzyme that is subject to negative-feedback regulation by sterols, in co-ordination with HMG-CoA reductase. Feeding mice on a tuna fish oil diet for 2 weeks decreased serum cholesterol and triacylglycerol levels, by 50% and 60% respectively. Hepatic levels of FPP synthase and HMG-CoA reductase mRNAs were also decreased, by 70% and 40% respectively. Individual n-3 and n-6 PUFA lowered FPP synthase and HMG-CoA reductase mRNA levels in H4IIEC3 rat hepatoma cells to a greater extent than did stearate and oleate, with the largest inhibitory effects occurring with arachidonate, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). We observed a similar inhibitory effect on protein levels of FPP synthase. The suppressive effect of PUFA on the FPP synthase mRNA level was not due to a decrease in mRNA stability, but to transcription inhibition. Moreover, a lower nuclear availability of both SREBP-1 and SREBP-2 mature forms was observed in HepG2 human hepatoblastoma cells treated with arachidonate, EPA or DHA. Taken together, these data suggest that PUFA can down-regulate hepatic cholesterol synthesis through inhibition of HMG-CoA reductase and FPP synthase, at least in part through impairment of the SREBP pathway.
Key words: farnesyl diphosphate synthase (FPP synthase), 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), fish oil diet, hepatoma cell, mouse liver, sterol regulatory element-binding protein (SREBP).
Abbreviations used: AOX, acyl-CoA oxidase; CMV, cytomegalovirus; DHA, docosahexaenoic acid; DMEM, Dulbecco's modified Eagle's medium; DRB, 5,6-dichlorobenzimidazole riboside; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; FPP synthase, farnesyl diphosphate synthase (geranyl-diphosphate geranyltranstransferase); HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA reductase; HSC70, heat-shock cognate 70 stress protein; LXR, liver X receptor; PPARa, peroxisome-proliferator-activated receptor a; PUFA, polyunsaturated fatty acids; RT-PCR, reverse transcription–PCR; SRE, sterol response element; SREBP, sterol regulatory element-binding protein; SCAP, SREBP cleavage-activating protein.
1To whom correspondence should be sent, at present address: EA948, Faculté de Médecine, 22 Avenue Camille Desmoulins, 29238 Brest cedex 3, France (email catherine.corcos@univ-brest.fr).
Received 3 June 2004/27 September 2004; accepted 8 October 2004
Published as BJ Immediate Publication 8 October 2004, DOI 10.1042/BJ20040933
The Biochemical Society, London ©2005
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