Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet
Background: Dietary intake of cereal fiber has been reported to benefit lipid metabolism through multiple mechanisms. The present study aimed to discover the potential mechanisms by which cereal fiber could modify the intestinal cholesterol metabolism.
Design: Male C57BL/6 mice were fed a reference chow (RC) diet; high-fat, high-cholesterol (HFC) diet; HFC plus oat fiber diet; or HFC plus wheat bran fiber diet for 24 weeks. Serum lipids were measured by enzymatic methods. Western blot was used to determine the protein expressions involved in intestinal cholesterol metabolism.
Results: Our results showed that HFC-induced elevations of serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol were normalized in both groups that received cereal fiber. At the protein level, compared with the HFC diet group, the two cereal fibers, especially the oat fiber, significantly increased the protein expression of peroxisome proliferator-activated receptor alpha, liver X receptor alpha, sterol regulatory element- binding protein (SREBP) 2, low-density lipoprotein receptor, adenosine triphosphate (ATP)-binding cassette A1, and ATP-binding cassette G1, while decreasing the protein expression of Niemann-Pick C1-like protein 1, SREBP-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, which were involved in intestinal cholesterol metabolism.
Conclusion: Taken together, increased intake of cereal fiber improved blood cholesterol profiles and increased the intestinal cholesterol efflux and cholesterol clearance in C57BL/6 mice fed a HFC diet. Oat fiber had a stronger effect than wheat bran fiber on cholesterol metabolism by modulating the PPARα, LXRα, and SREBP signaling pathways.
- National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–421. doi: 10.1161/circ.106.25.3143.
- Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, et al. 2012. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581–90. doi: 10.1016/S0140-6736(12)60367-5.
- Hartley L, May MD, Loveman E, Colquitt JL, Rees K. Dietary fibre for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2016; 7: CD011472. doi: 10.1002/14651858.
- Threapleton DE, Greenwood DC, Evans CE, Cleghorn CL, Nykjaer C, Woodhead C, et al. Dietary fiber intake and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2013; 19: 347. doi: 10.1136/bmj.f6879.
- Liu L, Wang S, Liu J. Fiber consumption and all-cause, cardiovascular, and cancer mortalities: a systematic review and meta-analysisof cohort studies. Mol Nutr Food Res 2015; 59: 139–46. doi: 10.1002/mnfr.201400449.
- Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, et al. Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 2004; 303: 1201–4. doi: 10.1126/science.1093131.
- Davis HR Jr, Hoos LM, Tetzloff G, Maguire M, Zhu LJ, Graziano MP, et al. Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE / mice. Arterioscler Thromb Vasc Biol 2007; 27: 841–9. doi: 10.1161/01.ATV.0000257627.40486.46.
- Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 1996; 383: 728–31. doi: 10.1038/383728a0.
- Ogata M, Tsujita M, Hossain MA, Akita N, Gonzalez FJ, Staels B, et al. On the mechanism for PPAR agonists to enhance ABCA1 gene expression. Atherosclerosis 2009; 205: 413–19. doi: 10.1016/j.atherosclerosis.2009.01.008.
- Valasek MA, Clarke SL, Repa JJ. Fenofibrate reduces intestinal cholesterol absorption via PPARalpha-dependent modulation of NPC1L1 expression in mouse. J Lipid Res 2007; 48: 2725–35. doi: 10.1194/jlr.M700345-JLR200.
- Han S, Jiao J, Zhang W, Xu J, Wan Z, Zhang W, et al. Dietary fiber prevents obesity-related liver lipotoxicity by modulating sterol-regulatory element binding protein pathway in C57BL/6J mice fed a high-fat/cholesterol diet. Sci Rep 2015; 5: 15256. doi: 10.1038/srep15256.
- Zhang R, Jiao J, Zhang W, Zhang Z, Zhang W, et al. Effects of cereal fiber on leptin resistance and sensitivity in C57BL/6J mice fed a high-fat/cholesterol diet. Food Nutr Res 2016; 60: 31690. doi: 10.3402/fnr.v60.31690.
- Zhou AL, Hergert N, Rompato G, Lefevre M. Whole grain oats improve insulin sensitivity and plasma cholesterol profile and modify gut microbiota composition in C57BL/6J mice. J Nutr 2015; 145: 222–30. doi 10.3945/jn.114.199778.
- Momenizadeh A, Heidari R, Sadeghi M, Tabesh F, Ekramzadeh M, Haghighatian Z, et al. Effects of oat and wheat bread consumption on lipid profile, blood sugar, and endothelial function in hypercholesterolemic patients: a randomized controlled clinical trial. ARYA Atheroscler 2014; 10: 259–65. ORCID: http://orcid.org/0000-0002-7994-8405.
- Othman RA, Moghadasian MH, Jones PJ. Cholesterol-lowering effects of oat β-glucan. Nutr Rev 2011; 69: 299–309. doi: 10.1111/j.1753-4887.
- Lund EK, Gee JM, Brown JC, Wood PJ, Johnson IT. Effect of oat gum on the physical properties of the gastrointestinal contents and on the uptake of D-galactose and cholesterol by rat small intestine in vitro. Br J Nutr 1989; 62: 91–101. doi: 10.1079/BJN19890010.
- Bell S, Goldman VM, Bistrian BR, Arnold AH, Ostroff G, Forse RA. Effect of beta-glucan from oats and yeast on serum lipids. Crit Rev Food Sci Nutr 1999; 39: 189–202. doi: 10.1080/10408399908500493.
- Hara H, Haga S, Aoyama Y, Kiriyama S. Short-chain fatty acids suppress cholesterol synthesis in rat liver and intestine. J Nutr 1999; 129: 942–8. doi: 10.1093/jn/129.5.942.
- Gunness P, Gidley MJ. Mechanisms underlying the cholesterol-lowering properties of soluble dietary fibre polysaccharides. Food Funct 2010; 1: 149–55. doi: 10.1039/c0fo00080a.
- Kesaniemi YA, Miettinen TA. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population. Eur J Clin Invest 1987; 17: 391–5. doi: 10.1111/j.1365-2362.1987.tb01132.x.
- Threapleton DE, Greenwood DC, Evans CEL, Cleghorn CL, Nykjaer C, Woodhead C, et al. Dietary fibre intake and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 2013; 347: f6879. doi: 10.1136/bmj.
- Shimano H. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 2001; 40: 439–52. doi: 10.1016/S0163-7827(01)00010-8.
- Daemen S, Kutmon M, Evelo CT. A pathway approach to investigate the function and regulation of SREBPs. Gene Nutr 2013; 8: 289–300. doi: 10.1007/s12263-013-0342-x.
- Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997; 89: 331–40. doi: 10.1016/S0092-8674(00)80213-5.
- Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, et al. Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res 2002; 43: 1220–35. doi: 10.1194/jlr.M100417-JLR200.
- Brown MS, Goldstein JL. Lowering plasma cholesterol by raising LDL receptors. New Engl J Med 1981; 305: 515–17. doi: 10.1056/NEJM198108273050909.
- Sato R. Sterol metabolism and SREBP activation. Arch Biochem Biophys 2010; 501: 177–81. doi: 10.1016/j.abb.2010.06.004.
- Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A. 2000; 97: 12097–102. doi: 10.1073/pnas.200367697.
- Smet M, Van Hoecke L, De Beuckelaer A, Vander Beken S, Naessens T, Vergote K, et al. Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice. Immun Inflamm Dis 2016; 4: 350–61. doi: 10.1002/iid3.118.
- Voloshyna I, Reiss AB. The ABC transporters in lipid flux and atherosclerosis. Prog Lipid Res 2011; 50: 213–24. doi: 10.1016/j.plipres.2011.02.001.
- Ma AZ, Song ZY, Zhang, Q. (2014). Cholesterol efflux is LXRα isoform-dependent in human macrophages. BMC Cardiovasc Disord 2014; 14: 80. doi: 10.1186/1471-2261-14-80.
- Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver receptors alpha and beta. J Biol Chem 2002; 277: 18793–800. doi: 10.1074/jbc.M109927200.
- Sané AT, Sinnett D, Delvin E, Bendayan M, Marcil V, Ménard D, et al. Localization and role of NPC1L1 in cholesterol absorption in human intestine. J Lipid Res 2006; 47: 2112–20. doi: 10.1194/jlr.M600174-JLR200.
- Xie C, Zhou ZS, Li N, Bian Y, Wang YJ, Wang LJ, et al. Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. J Lipid Res 2012; 53: 2092–101. doi: 10.1194/jlr.M027359.
- Sané A, Seidman E, Spahis S, Lamantia V, Garofalo C, Montoudis A, et al. New insights in intestinal Sar1B GTPase regulation and role in cholesterol homeostasis. J Cell Biochem 2015; 116: 2270–82. doi: 10.1002/jcb.25177.
- Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, et al. Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice. J Lipid Res 2013; 54: 1567–77. doi: 10.1194/jlr.M034454.
This work is licensed under a Creative Commons Attribution 4.0 International License
Authors retain copyright of their work, with first publication rights granted to SNF Swedish Nutrition Foundation.