Suppression of Fatty Acid Synthase by Dietary Polyunsaturated Fatty Acids is Mediated by Fat itself, not by Peroxidative Mechanism

Kim, Hye Kyeong; Choi, Sung Won; Lee, Hae Jeung; Lee, Joo Hee; Choi, Hay Mie

doi:10.5483/bmbrep.2003.36.3.258

Cited by 20 publications

(15 citation statements)

References 40 publications

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“…However, it is conceivable that the reduction in MCAD reflects a response to fatty acid chain length profile rather than lipid content per se. Food deprivation caused a marked reduction in FAS, consistent with a shift away from lipogenesis, as seen in other models (Field et al, 2003;Kim et al, 2003;Li et al, 2006;Paulauskis and Sul, 1988).…”

Section: Lipid Homeostasis Gene Expressionsupporting

confidence: 50%

Role of the PGC-1 family in the metabolic adaptation of goldfish to diet and temperature

LeMoine

Genge

Moyes

2008

Journal of Experimental Biology

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SUMMARYIn mammals, the peroxisome proliferator-activated receptor (PPAR) γ coactivator-1 (PGC-1) family members and their binding partners orchestrate remodelling in response to diverse challenges such as diet, temperature and exercise. In this study, we exposed goldfish to three temperatures (4, 20 and 35°C) and to three dietary regimes (food deprivation, low fat and high fat) and examined the changes in mitochondrial enzyme activities and transcript levels for metabolic enzymes and their genetic regulators in red muscle, white muscle, heart and liver. When all tissues and conditions were pooled, there were significant correlations between the mRNA for the PGC-1 coactivators (both α and β) and mitochondrial transcripts (citrate synthase), metabolic gene regulators including PPARα, PPARβ and nuclear respiratory factor-1 (NRF-1). PGC-1β was the better predictor of the NRF-1 axis, whereas PGC-1α was the better predictor of the PPAR axis (PPARα, PPARβ, medium chain acyl CoA dehydrogenase). In contrast to these intertissue/developmental patterns, the response of individual tissues to physiological stressors displayed no correlations between mRNA for PGC-1 family members and either the NRF-1 or PPAR axes. For example, in skeletal muscles, low temperature decreased PGC-1α transcript levels but increased mitochondrial enzyme activities (citrate synthase and cytochrome oxidase) and transcripts for COX IV and NRF-1. These results suggest that in goldfish, as in mammals, there is a regulatory relationship between (i) NRF-1 and mitochondrial gene expression and (ii) PPARs and fatty acid oxidation gene expression. In contrast to mammals, there is a divergence in the roles of the coactivators, with PGC-1α linked to fatty acid oxidation through PPARα, and PGC-1β with a more prominent role in mediating NRF-1-dependent control of mitochondrial gene expression, as well as distinctions between their respective roles in development and physiological responsiveness.

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Section: Lipid Homeostasis Gene Expressionsupporting

confidence: 50%

Role of the PGC-1 family in the metabolic adaptation of goldfish to diet and temperature

LeMoine

Genge

Moyes

2008

Journal of Experimental Biology

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“…Feeding full-fat canola seeds has also reduced levels of C16:0 and C16:1 in beef tissues (St. John et al 1987;Rule et al 1994). Sixteen C fatty acids are commonly reduced in deposited fat when oils are supplemented in the diet (Markus et al 1996;Mir et al 2003b;Gibb et al 2004), a response that likely reflects reduced de novo fatty acid synthesis in tissues (Kim et al 2003;Vernon 1976) and/or dilution resulting from increased levels of 18 C fatty acids.…”

Section: Fatty Acidsmentioning

confidence: 99%

Effect of full-fat hemp seed on performance and tissue fatty acids of feedlot cattle

Gibb¹,

Shah²,

Mir³

et al. 2005

Can. J. Anim. Sci.

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. 2005. Effect of full-fat hemp seed on performance and tissue fatty acids of feedlot cattle. Can. J. Anim. Sci. 85: 223-230. Sixty individually penned steers (380 ± 39 kg) were fed barley-based finishing diets containing 0 (control), 9 or 14% full-fat hemp seed (HS) and effects on performance and tissue fatty acid profiles were assessed. At harvest, samples of pars costalis diaphragmatis (PCD) and brisket fat were collected from each carcass. Feeding HS did not affect (P > 0.25) dry matter intake (DMI), average daily gain (ADG), or gain feed -1 . Carcass traits were also unaffected (P > 0.35) by treatment. Feeding HS linearly increased (P < 0.001) proportions of C18:0, C18:3 and C18:1 trans-9 in PCD, and 18:2 trans, trans in both PCD and brisket fat. As well, HS linearly increased cis-9 trans-11 CLA (P < 0.001), total saturates (P = 0.002) and polyunsaturated fatty acids (PUFA) (P = 0.01) in PCD. The presence of C20:4, C20:5 and C22:5 was detected only in tissues of cattle supplemented with HS (P < 0.06). Linear reductions (P < 0.002) in C16:1 cis, C17:1, C18:1 cis-9, C20:1, and total unsaturates in PCD, as well as linear decreases in C17:0 (P = 0.04) and C17:1 (P < 0.001) in brisket fat were observed when HS was fed. Levels of HS up to 14% of dietary DM exerted no detrimental effect on the growth or feed efficiency of cattle as compared to cattle fed a standard barley-based finishing diet. Including HS in the diet had both positive (increased CLA content) and negative (increased trans and saturated fats) effects on fatty acid profiles of beef tissues. Soixante bouvillons (380 ± 39 kg) gardés dans des enclos distincts ont reçu une ration de finition à base d'orge contenant 0 (témoin), 9 ou 14 % de graines de chanvre non délipidées (HS). On a étudié l'incidence d'une telle ration sur le rendement et la composition des acides gras dans les tissus. À l'abattage, on a prélevé des échantillons du gras du pars costalis diaphragmatis (PCD) et de la pointe de poitrine de chaque carcasse. L'ingestion de HS ne modifie pas (P > 0,25) l'ingestion de matière sèche, le gain quotidien moyen ni le gain selon le type d'aliment. Les paramètres de la carcasse ne sont pas affectés (P > 0,35) non plus par le traitement. L'ingestion de HS accroît de façon linéaire (P < 0,001) la proportion de C18:0, de C18:3 et de C18:1 trans-9 dans le PCD et de 18:2 trans, trans dans le PCD et la pointe de poitrine. Le HS augmente aussi linéairement la quantité d'acide linoléique conjugué cis-9-trans-11 (P < 0,001), d'acides gras saturés totaux (P = 0,002) et d'acides gras polyinsaturés (P = 0,01) dans le PCD. On n'a décelé la présence de C20:4, de C20:5 et de C22:5 que dans les tissus des bovins à qui on avait donné du HS (P < 0,06). L'administration de HS entraîne une diminution linéaire (P < 0,002) du C16:1 cis, du C17:1, du C18:1 cis-9, du C20:1 et de l'ensemble des acides gras insaturés dans le PCD ainsi qu'une baisse linéaire du C17:0 (P = 0,04) et du C17:1 (P < 0,001) dans le gras de la pointe de poitrine. Jusqu'à concurrence de 14 % de la m...

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“…A popular but controversial view is that the cytotoxic and antiproliferative effects of exogenous GLA or ALA are due to formation of peroxidation products that could then inhibit FAS (13,22). On the other hand, experimental data showed that PUFAs themselves are responsible for FAS suppression (23). To further our molecular understanding of these issues, we carried out structural and biochemical studies of the 32 kDa TE domain of hFAS covalently modified by a methylfluorophosphonate head group linked to a γ-linolenyl acyl tail and, prompted by the results, investigated the inhibitions of related PUFAs on the TE activity, fatty acid biosynthesis in 3T3-L1 preadipocytes and human breast cancer cell lines.…”

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confidence: 99%

Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-γ-linolenic acid

Zhang

Chakravarty

Zheng

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Human fatty acid synthase (hFAS) is a homodimeric multidomain enzyme that catalyzes a series of reactions leading to the de novo biosynthesis of long-chain fatty acids, mainly palmitate. The carboxy-terminal thioesterase (TE) domain determines the length of the fatty acyl chain and its ultimate release by hydrolysis. Because of the upregulation of hFAS in a variety of cancers, it is a target for antiproliferative agent development. Dietary long-chain polyunsaturated fatty acids (PUFAs) have been known to confer beneficial effects on many diseases and health conditions, including cancers, inflammations, diabetes, and heart diseases, but the precise molecular mechanisms involved have not been elucidated. We report the 1.48 Å crystal structure of the hFAS TE domain covalently modified and inactivated by methyl γ-linolenylfluorophosphonate. Whereas the structure confirmed the phosphorylation by the phosphonate head group of the active site serine, it also unexpectedly revealed the binding of the 18-carbon polyunsaturated γ-linolenyl tail in a long groove-tunnel site, which itself is formed mainly by the emergence of an α helix (the "helix flap"). We then found inhibition of the TE domain activity by the PUFA dihomo-γ-linolenic acid; γ-and α-linolenic acids, two popular dietary PUFAs, were less effective. Dihomo-γ-linolenic acid also inhibited fatty acid biosynthesis in 3T3-L1 preadipocytes and selective human breast cancer cell lines, including SKBR3 and MDAMB231. In addition to revealing a novel mechanism for the molecular recognition of a polyunsaturated fatty acyl chain, our results offer a new framework for developing potent FAS inhibitors as therapeutics against cancers and other diseases.X-ray crystallography | conformational change | fatty acid selectivity | two-subdomain binding site

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Suppression of Fatty Acid Synthase by Dietary Polyunsaturated Fatty Acids is Mediated by Fat itself, not by Peroxidative Mechanism

Cited by 20 publications

References 40 publications

Role of the PGC-1 family in the metabolic adaptation of goldfish to diet and temperature

Role of the PGC-1 family in the metabolic adaptation of goldfish to diet and temperature

Effect of full-fat hemp seed on performance and tissue fatty acids of feedlot cattle

Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-γ-linolenic acid

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