Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids

Abstract

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.

Eicosapentaenoic acid lowers plasma and liver cholesterol levels in the presence of peroxisome proliferators-activated receptor alpha

“…Our trial to identify key molecules in the EPA function on SREBP-2 processing has been unsuccessful so far, which leads us to reconsider roles of EPA. At present, a likely hypothesis is that EPA may modify membrane fluidity, which could be followed by enrichment in cholesterol in order to preserve membrane stability, as described by Le Jossic-Corcos et al (2005). The change in membrane fluidity could inhibit escorting the SREBP cleavage activating protein-SREBP-2 complex from endoplasmic reticulum to the Golgi apparatus, where the proteolytic processing occurs.…”

“…The mechanisms of their lipid-lowering effects have been tentatively established (Field et al, 2002;Yoshikawa et al, 2002;Davidson, 2006). EPA is currently used as a hypolipidemic drug, ethyl all-cis-5,8,11,14,17-icosapentaenoate, and is demonstrated to modulate gene expression in lipid and glucose homeostasis (Jump et al, 1994;Field et al, 2002;Le Jossic-Corcos et al, 2005). The hypotriglycemic effect of EPA mainly results from the combined effects of the inhibition of lypogenesis, and the stimulation of fatty acid oxidation in liver (Ren et al, 1997;Yahagi et al, 1999;Clarke, 2001;Jump et al, 2005).…”

“…In contrast, the mechanism of hypocholesterolemic effect of EPA is not fully understood. Several studies described that EPA inhibited expression or activities of hepatic cholesterol biosynthesis (Mizuguchi et al, 1993;Kim et al, 1999;Le Jossic-Corcos et al, 2005). Additionally, EPA also suppressed intestinal cholesterol absorption and enhanced hepatic biliary secretion (Mizuguchi et al, 1993;Ramaprasad et al, 2006).…”

Dietary Starfish Oil Prevents Hepatic Steatosis and Hyperlipidemia in C57BL/6N Mice Fed High-fat Diet

“…SREBP also regulates the transcription of cholesterol synthesis enzymes, such as 3-hydroxy-3-methylglutarylCoA reductase HMG-CoA reductase , the rate-limiting enzyme. N-3 PUFA is known to improve cholesterol and lipoprotein metabolism 41,42 , and its hypocholesterolemic effect is mainly due to suppression of HMG-CoA reductase at the transcriptional level 43,44 . Le Jossic-Corcos and others showed that EPA and DHA exhibit inhibitory effects on cholesterol production through reduction of these genes in human hepatoma HepG2 cells, and suggested that such negative effects occur as a result of downregulation of SREBP gene expression.…”

Natural Cholesterol Busters

“…The ω3-PUFAs have been shown to increase plasma LDL with large particle size, which is much less atherogenic than LDL that cannot infiltrate blood vessels of vascular endothelium to start development of atherosclerosis [24]. Moreover, ω3-PUFAs downregulate sterol regulatory element-binding protein, resulting in suppression of gene expression of 3-hydroxy-3-methyl-glutaryl CoA reductase, a rate-limiting enzyme in cholesterol synthesis [25]. ω3-PUFAs also activate liver X receptors that upregulate expression of 7-α-hydroxylase, the main enzyme in conversion of cholesterol into bile acids [26].…”