Abstract
Purpose
To investigate the mechanism implicated in the effect of an insoluble fiber (obtained from carob pod) rich in polyphenols (IFCP) in lipid metabolism in the liver.
Methods
Male New Zealand rabbits were fed with the following diets for 8 weeks: control diet (CT group), dyslipidemic diet supplemented with 0.5% cholesterol + 14% coconut oil (DL group) and dyslipidemic diet containing 0.5% cholesterol + 14% coconut oil plus 3% IFCP (DL + IFCP group).
Results
Dyslipidemic diet with IFCP was able to reduce development of mixed dyslipidemia, liver relative weight and collagen I protein expression compared to DL rabbits. Analyses of the main enzymes implicated in cholesterol and triglycerides metabolism revealed that IFCP increased hepatic concentration of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and cytochrome P450, family 7, subfamily a, polypeptide 1C (CYP7A1) (82.34, 114.42%, respectively) as well as protein expression of LDL receptor (42.48%) in DL rabbits. Importantly, IFCP also increased hepatic lipase (HL) levels (91.43%) and decreased glycerol phosphate acyltransferase (GPAT) and sterol regulatory element-binding protein 1C (SREBP1c) liver expression levels (20.38 and 41.20%, respectively). Finally, sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) hepatic expression increased in DL + IFCP group compared with DL (159.81 and 48.00%, respectively).
Conclusions
These findings show that IFCP is able to abrogate the deleterious effects of hepatic dyslipidemia by modulating SIRT1 and PGC-1α pathways.
Similar content being viewed by others
Abbreviations
- CYP7A1:
-
Cytochrome P450, family 7, subfamily a, polypeptide 1C
- FXR:
-
Farnesoid x receptor
- GPAT:
-
Glycerol phosphate acyltransferase
- HL:
-
Hepatic lipase
- HMG-CoA reductase:
-
3-Hydroxy-3-methylglutaryl-CoA reductase
- LDLR:
-
LDL receptor
- LXR:
-
Liver x receptor
- PGC-1α:
-
Peroxisome proliferator-activated receptor gamma coactivator-1alpha
- PPAR:
-
Peroxisome proliferator-activated receptor
- SIRT1:
-
Sirtuin1
- SREBP-1C:
-
Sterol regulatory element-binding protein 1C
References
Vazzana N, Santilli F, Sestili S, Cuccurullo C, Davi G (2011) Determinants of increased cardiovascular disease in obesity and metabolic syndrome. Curr Med Chem 18(34):5267–5280
Recinos A 3rd, Carr BK, Bartos DB, Boldogh I, Carmical JR, Belalcazar LM, Brasier AR (2004) Liver gene expression associated with diet and lesion development in atherosclerosis-prone mice: induction of components of alternative complement pathway. Physiol Genom 19(1):131–142. https://doi.org/10.1152/physiolgenomics.00146.2003
Moore KJ, Rayner KJ, Suarez Y, Fernandez-Hernando C (2010) microRNAs and cholesterol metabolism. Trends Endocrinol Metab 21(12):699–706. https://doi.org/10.1016/j.tem.2010.08.008
Anderson N, Borlak J (2008) Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 60(3):311–357. https://doi.org/10.1124/pr.108.00001
Panda T, Devi VA (2004) Regulation and degradation of HMGCo-A reductase. Appl Microbiol Biotechnol 66(2):143–152. https://doi.org/10.1007/s00253-004-1720-5
DeBose-Boyd RA (2008) Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18(6):609–621. https://doi.org/10.1038/cr.2008.61
Zou Y, Du H, Yin M, Zhang L, Mao L, Xiao N, Ren G, Zhang C, Pan J (2009) Effects of high dietary fat and cholesterol on expression of PPAR alpha, LXR alpha, and their responsive genes in the liver of apoE and LDLR double deficient mice. Mol Cell Biochem 323(1–2):195–205. https://doi.org/10.1007/s11010-008-9982-3
Kim EJ, Kim E, Kwon EY, Jang HS, Hur CG, Choi MS (2010) Network analysis of hepatic genes responded to high-fat diet in C57BL/6J mice: nutrigenomics data mining from recent research findings. J Med Food 13(4):743–756. https://doi.org/10.1089/jmf.2009.1350
Redinger RN (2003) Nuclear receptors in cholesterol catabolism: molecular biology of the enterohepatic circulation of bile salts and its role in cholesterol homeostasis. J Lab Clin Med 142(1):7–20. https://doi.org/10.1016/S0022-2143(03)00088-X
Caiozzi G, Wong BS, Ricketts ML (2012) Dietary modification of metabolic pathways via nuclear hormone receptors. Cell Biochem Funct 30(7):531–551. https://doi.org/10.1002/cbf.2842
Zschoernig B, Mahlknecht U (2008) SIRTUIN 1: regulating the regulator. Biochem Biophys Res Commun 376(2):251–255. https://doi.org/10.1016/j.bbrc.2008.08.137
Schug TT, Li X (2011) Sirtuin 1 in lipid metabolism and obesity. Ann Med 43(3):198–211. https://doi.org/10.3109/07853890.2010.547211
Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582(1):46–53. https://doi.org/10.1016/j.febslet.2007.11.034
Dominy JE Jr, Lee Y, Gerhart-Hines Z, Puigserver P (2010) Nutrient-dependent regulation of PGC-1alpha’s acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim Biophys Acta 1804(8):1676–1683. https://doi.org/10.1016/j.bbapap.2009.11.023
Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413(6852):131–138. https://doi.org/10.1038/35093050
Gu C, Zeng Y, Tang Z, Wang C, He Y, Feng X, Zhou L (2015) Astragalus polysaccharides affect insulin resistance by regulating the hepatic SIRT1-PGC-1alpha/PPARalpha-FGF21 signaling pathway in male Sprague Dawley rats undergoing catch-up growth. Mol Med Rep 12(5):6451–6460. https://doi.org/10.3892/mmr.2015.4245
Lieber CS, Leo MA, Wang X, Decarli LM (2008) Effect of chronic alcohol consumption on Hepatic SIRT1 and PGC-1alpha in rats. Biochem Biophys Res Commun 370(1):44–48. https://doi.org/10.1016/j.bbrc.2008.03.005
You M, Liang X, Ajmo JM, Ness GC (2008) Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 294(4):G892–G898. https://doi.org/10.1152/ajpgi.00575.2007
Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, Wassertheil-Smoller S, Kuller LH, LaCroix AZ, Langer RD, Lasser NL, Lewis CE, Limacher MC, Margolis KL, Mysiw WJ, Ockene JK, Parker LM, Perri MG, Phillips L, Prentice RL, Robbins J, Rossouw JE, Sarto GE, Schatz IJ, Snetselaar LG, Stevens VJ, Tinker LF, Trevisan M, Vitolins MZ, Anderson GL, Assaf AR, Bassford T, Beresford SA, Black HR, Brunner RL, Brzyski RG, Caan B, Chlebowski RT, Gass M, Granek I, Greenland P, Hays J, Heber D, Heiss G, Hendrix SL, Hubbell FA, Johnson KC, Kotchen JM (2006) Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295(6):655–666. https://doi.org/10.1001/jama.295.6.655
Papanikolaou Y, Fulgoni VL 3rd (2008) Bean consumption is associated with greater nutrient intake, reduced systolic blood pressure, lower body weight, and a smaller waist circumference in adults: results from the National Health and Nutrition Examination Survey 1999–2002. J Am Coll Nutr 27(5):569–576
Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pinto X, Basora J, Munoz MA, Sorli JV, Martinez JA, Martinez-Gonzalez MA, Investigators PS (2013) Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 368(14):1279–1290. https://doi.org/10.1056/NEJMoa1200303
Wursch P (1979) Influence of tannin-rich carob pod fiber on the cholesterol metabolism in the rat. J Nutr 109(4):685–692
Zunft HJ, Luder W, Harde A, Haber B, Graubaum HJ, Koebnick C, Grunwald J (2003) Carob pulp preparation rich in insoluble fibre lowers total and LDL cholesterol in hypercholesterolemic patients. Eur J Nutr 42(5):235–242. https://doi.org/10.1007/s00394-003-0438-y
Ruiz-Roso B, Quintela JC, de la Fuente E, Haya J, Perez-Olleros L (2010) Insoluble carob fiber rich in polyphenols lowers total and LDL cholesterol in hypercholesterolemic sujects. Plant Foods Hum Nutr 65(1):50–56. https://doi.org/10.1007/s11130-009-0153-9
Proenca LM, Mayer J (2014) Prescription diets for rabbits. Vet Clin N Am Exot Anim Pract 17(3):485–502. https://doi.org/10.1016/j.cvex.2014.05.009
Papagiannopoulos M, Wollseifen HR, Mellenthin A, Haber B, Galensa R (2004) Identification and quantification of polyphenols in carob fruits (Ceratonia siliqua L.) and derived products by HPLC-UV-ESI/MSn. J Agric Food Chem 52(12):3784–3791. https://doi.org/10.1021/jf030660y
Bastida S, Sanchez-Muniz FJ, Olivero R, Perez-Olleros L, Ruiz-Roso B, Jimenez-Colmenero F (2009) Antioxidant activity of Carob fruit extracts in cooked pork meat systems during chilled and frozen storage. Food Chem 116(3):748–754. https://doi.org/10.1016/j.foodchem.2009.03.034
Russo MA, Sansone L, Polletta L, Runci A, Rashid MM, De Santis E, Vernucci E, Carnevale I, Tafani M (2014) Sirtuins and resveratrol-derived compounds: a model for understanding the beneficial effects of the Mediterranean diet. Endocr Metab Immune Disord Drug Targets 14(4):300–308
Eo H, Jeon YJ, Lee M, Lim Y (2015) Brown Alga Ecklonia cava polyphenol extract ameliorates hepatic lipogenesis, oxidative stress, and inflammation by activation of AMPK and SIRT1 in high-fat diet-induced obese mice. J Agric Food Chem 63(1):349–359. https://doi.org/10.1021/jf502830b
Ruiz-Roso B, Quintela JC, de la Fuente E, Haya J, Perez-Olleros L (2010) Insoluble carob fiber rich in polyphenols lowers total and LDL cholesterol in hypercholesterolemic subjects. Plant Food Hum Nutr 65(1):50–56. https://doi.org/10.1007/s11130-009-0153-9
Gomez-Hernandez A, Otero YF, de las Heras N, Escribano O, Cachofeiro V, Lahera V, Benito M (2012) Brown fat lipoatrophy and increased visceral adiposity through a concerted adipocytokines overexpression induces vascular insulin resistance and dysfunction. Endocrinology 153(3):1242–1255. https://doi.org/10.1210/en.2011-1765
Valero-Munoz M, Martin-Fernandez B, Ballesteros S, Martinez-Martinez E, Blanco-Rivero J, Balfagon G, Cachofeiro V, Lahera V, de las Heras N (2013) Relevance of vascular peroxisome proliferator-activated receptor gamma coactivator-1alpha to molecular alterations in atherosclerosis. Exp Physiol 98(5):999–1008. https://doi.org/10.1113/expphysiol.2012.070557
Teodoro JS, Rolo AP, Palmeira CM (2011) Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metab 22(11):458–466. https://doi.org/10.1016/j.tem.2011.07.002
Cote I, Ngo Sock ET, Levy E, Lavoie JM (2013) An atherogenic diet decreases liver FXR gene expression and causes severe hepatic steatosis and hepatic cholesterol accumulation: effect of endurance training. Eur J Nutr 52(5):1523–1532. https://doi.org/10.1007/s00394-012-0459-5
Rodgers JT, Puigserver P (2007) Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci USA 104(31):12861–12866. https://doi.org/10.1073/pnas.0702509104
Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9(4):327–338. https://doi.org/10.1016/j.cmet.2009.02.006
Rhee J, Ge H, Yang W, Fan M, Handschin C, Cooper M, Lin J, Li C, Spiegelman BM (2006) Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism. J Biol Chem 281(21):14683–14690. https://doi.org/10.1074/jbc.M512636200
Weber TE, Trabue SL, Ziemer CJ, Kerr BJ (2010) Evaluation of elevated dietary corn fiber from corn germ meal in growing female pigs. J Anim Sci 88(1):192–201. https://doi.org/10.2527/jas.2009-1896
You M, Cao Q, Liang X, Ajmo JM, Ness GC (2008) Mammalian sirtuin 1 is involved in the protective action of dietary saturated fat against alcoholic fatty liver in mice. J Nutr 138(3):497–501
Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK (2010) SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 285(44):33959–33970. https://doi.org/10.1074/jbc.M110.122978
Wang S, Moustaid-Moussa N, Chen L, Mo H, Shastri A, Su R, Bapat P, Kwun I, Shen CL (2014) Novel insights of dietary polyphenols and obesity. J Nutr Biochem 25(1):1–18. https://doi.org/10.1016/j.jnutbio.2013.09.001
Lomb DJ, Laurent G, Haigis MC (2010) Sirtuins regulate key aspects of lipid metabolism. Biochim Biophys Acta 1804(8):1652–1657. https://doi.org/10.1016/j.bbapap.2009.11.021
Shimano H (2009) SREBPs: physiology and pathophysiology of the SREBP family. FEBS J 276(3):616–621. https://doi.org/10.1111/j.1742-4658.2008.06806.x
Ferre P, Foufelle F (2007) SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 68(2):72–82. https://doi.org/10.1159/000100426
Wang Y, Viscarra J, Kim SJ, Sul HS (2015) Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol 16(11):678–689. https://doi.org/10.1038/nrm4074
Ejaz A, Wu D, Kwan P, Meydani M (2009) Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. J Nutr 139(5):919–925. https://doi.org/10.3945/jn.108.100966
Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM (2003) Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA 100(7):4012–4017. https://doi.org/10.1073/pnas.0730870100
Shin DJ, Campos JA, Gil G, Osborne TF (2003) PGC-1alpha activates CYP7A1 and bile acid biosynthesis. J Biol Chem 278(50):50047–50052. https://doi.org/10.1074/jbc.M309736200
Li X, Lian F, Liu C, Hu KQ, Wang XD (2015) Isocaloric pair-fed high-carbohydrate diet induced more hepatic steatosis and inflammation than high-fat diet mediated by miR-34a/SIRT1 axis in mice. Sci Rep 5:16774. https://doi.org/10.1038/srep16774
Kazgan N, Metukuri MR, Purushotham A, Lu J, Rao A, Lee S, Pratt-Hyatt M, Lickteig A, Csanaky IL, Zhao Y, Dawson PA, Li X (2014) Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1alpha-FXR signaling and alters systemic bile acid homeostasis. Gastroenterology 146(4):1006–1016. https://doi.org/10.1053/j.gastro.2013.12.029
Liaset B, Hao Q, Jorgensen H, Hallenborg P, Du ZY, Ma T, Marschall HU, Kruhoffer M, Li R, Li Q, Yde CC, Criales G, Bertram HC, Mellgren G, Ofjord ES, Lock EJ, Espe M, Froyland L, Madsen L, Kristiansen K (2011) Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. J Biol Chem 286(32):28382–28395. https://doi.org/10.1074/jbc.M111.234732
Henkel AS, Anderson KA, Dewey AM, Kavesh MH, Green RM (2011) A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice. J Lipid Res 52(2):289–298. https://doi.org/10.1194/jlr.M012781
Fukushima M, Nakano M, Morii Y, Ohashi T, Fujiwara Y, Sonoyama K (2000) Hepatic LDL receptor mRNA in rats is increased by dietary mushroom (Agaricus bisporus) fiber and sugar beet fiber. J Nutr 130(9):2151–2156
Fukushima M, Ohashi T, Fujiwara Y, Sonoyama K, Nakano M (2001) Cholesterol-lowering effects of maitake (Grifola frondosa) fiber, shiitake (Lentinus edodes) fiber, and enokitake (Flammulina velutipes) fiber in rats. Exp Biol Med (Maywood) 226(8):758–765
Ramjiganesh T, Roy S, Freake HC, McIntyre JC, Fernandez ML (2002) Corn fiber oil lowers plasma cholesterol by altering hepatic cholesterol metabolism and up-regulating LDL receptors in guinea pigs. J Nutr 132(3):335–340
Shibata S, Hayakawa K, Egashira Y, Sanada H (2007) Roles of nuclear receptors in the up-regulation of hepatic cholesterol 7alpha-hydroxylase by cholestyramine in rats. Life Sci 80(6):546–553. https://doi.org/10.1016/j.lfs.2006.10.003
Saura-Calixto F, Perez-Jimenez J, Tourino S, Serrano J, Fuguet E, Torres JL, Goni I (2010) Proanthocyanidin metabolites associated with dietary fibre from in vitro colonic fermentation and proanthocyanidin metabolites in human plasma. Mol Nutr Food Res 54(7):939–946. https://doi.org/10.1002/mnfr.200900276
Owen RW, Haubner R, Hull WE, Erben G, Spiegelhalder B, Bartsch H, Haber B (2003) Isolation and structure elucidation of the major individual polyphenols in carob fibre. Food Chem Toxicol 41(12):1727–1738
Funding
This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología de España [SAF2011-30396] and Ministerio de Ciencia e Innovación [IPT-2012-0213-060000].
Author information
Authors and Affiliations
Contributions
MV-M: conceived and designed the experiments; performed the experiments; analyzed the data; wrote the paper. SB: performed the experiments; analyzed the data. BRR: conceived and designed the experiments; analyzed the data and wrote the materials and methods. LP-O: conceived and designed the experiments; analyzed the data. BM-F: conceived and designed the experiments; analyzed the data. VL: conceived and designed the experiments; analyzed the data; wrote the paper. NH: conceived and designed the experiments; performed the experiments; analyzed the data; wrote the paper. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interest.
Rights and permissions
About this article
Cite this article
Valero-Muñoz, M., Ballesteros, S., Ruiz-Roso, B. et al. Supplementation with an insoluble fiber obtained from carob pod (Ceratonia siliqua L.) rich in polyphenols prevents dyslipidemia in rabbits through SIRT1/PGC-1α pathway. Eur J Nutr 58, 357–366 (2019). https://doi.org/10.1007/s00394-017-1599-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00394-017-1599-4