Plasma levels of triacylglycerols and diacylglycerols, the lipoproteins that transport them, and proteins involved in their absorption from the intestinal lumen fluctuate in a circadian manner. These changes are likely controlled by clock genes expressed in the intestine that are probably synchronized by neuronal and humoral signals from the suprachiasmatic nuclei, which constitute a master clock entrained by light signals from the eyes and from the environment, e.g., food availability. Acute changes in circadian rhythms—e.g., due to nonsynchronous work schedules or a transcontinental flight—may trigger intestinal discomfort. Chronic disruptions in circadian control mechanisms may predispose the individual to irritable bowel syndrome, gastroesophageal reflux disease, and peptic ulcer disease. A more detailed understanding of the molecular mechanisms underlying temporal changes in intestinal activity might allow us to identify novel targets for developing therapeutic approaches to these disorders.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Abumrad N, Harmon C, Ibrahimi A. 1.  1998. Membrane transport of long-chain fatty acids: evidence for a facilitated process. J. Lipid Res. 39:2309–18 [Google Scholar]
  2. Abumrad NA, Davidson NO. 2.  2012. Role of the gut in lipid homeostasis. Physiol. Rev. 92:1061–85 [Google Scholar]
  3. Bass J. 3.  2012. Circadian topology of metabolism. Nature 491:348–56 [Google Scholar]
  4. Bechtold DA, Loudon AS. 4.  2013. Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci. 36:74–82 [Google Scholar]
  5. Black DD. 5.  2007. Development and physiological regulation of intestinal lipid absorption. I. Development of intestinal lipid absorption: cellular events in chylomicron assembly and secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 293:G519–24 [Google Scholar]
  6. Bray MS, Young ME. 6.  2011. Regulation of fatty acid metabolism by cell autonomous circadian clocks: time to fatten up on information?. J. Biol. Chem. 286:11883–89 [Google Scholar]
  7. Brunham LR, Kruit JK, Iqbal J, Fievet C, Timmins JA. 7.  et al. 2006. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J. Clin. Invest. 116:1052–62 [Google Scholar]
  8. Cagampang FR, Bruce KD. 8.  2012. The role of the circadian clock system in nutrition and metabolism. Br. J. Nutr. 108:381–92 [Google Scholar]
  9. Campos H, Khoo C, Sacks FM. 9.  2005. Diurnal and acute patterns of postprandial apolipoprotein B-48 in VLDL, IDL, and LDL from normolipidemic humans. Atherosclerosis 181:345–51 [Google Scholar]
  10. Chua EC, Shui G, Lee IT, Lau P, Tan LC. 10.  et al. 2013. Extensive diversity in circadian regulation of plasma lipids and evidence for different circadian metabolic phenotypes in humans. Proc. Natl. Acad. Sci. USA 110:14468–73 [Google Scholar]
  11. Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. 11.  2012. The human circadian metabolome. Proc. Natl. Acad. Sci. USA 109:2625–29 [Google Scholar]
  12. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. 12.  2000. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14:2950–61 [Google Scholar]
  13. Dibner C, Schibler U, Albrecht U. 13.  2010. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72:517–49 [Google Scholar]
  14. Escobar C, Díaz-Muñoz M, Encinas F, Aguilar-Roblero R. 14.  1998. Persistence of metabolic rhythmicity during fasting and its entrainment by restricted feeding schedules in rats. Am. J. Physiol. 274:R1309–16 [Google Scholar]
  15. Feillet CA, Albrecht U, Challet E. 15.  2006. “Feeding time” for the brain: a matter of clocks. J. Physiol. Paris 100:252–60 [Google Scholar]
  16. Fukagawa K, Gou HM, Wolf R, Tso P. 16.  1994. Circadian rhythm of serum and lymph apolipoprotein AIV in ad libitum-fed and fasted rats. Am. J. Physiol. 267:R1385–90 [Google Scholar]
  17. Gerber A, Esnault C, Aubert G, Treisman R, Pralong F, Schibler U. 17.  2013. Blood-borne circadian signal stimulates daily oscillations in actin dynamics and SRF activity. Cell 152:492–503 [Google Scholar]
  18. Green CB, Takahashi JS, Bass J. 18.  2008. The meter of metabolism. Cell 134:728–42 [Google Scholar]
  19. Hara R, Wan K, Wakamatsu H, Aida R, Moriya T. 19.  et al. 2001. Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus. Genes Cells 6:269–78 [Google Scholar]
  20. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K. 20.  et al. 2007. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450:1086–90 [Google Scholar]
  21. Hoogerwerf WA. 21.  2006. Biologic clocks and the gut. Curr. Gastroenterol. Rep. 8:353–59 [Google Scholar]
  22. Hoogerwerf WA. 22.  2010. Role of clock genes in gastrointestinal motility. Am. J. Physiol. Gastrointest. Liver Physiol. 299:G549–55 [Google Scholar]
  23. Hoogerwerf WA, Hellmich HL, Cornelissen G, Halberg F, Shahinian VB. 23.  et al. 2007. Clock gene expression in the murine gastrointestinal tract: endogenous rhythmicity and effects of a feeding regimen. Gastroenterology 133:1250–60 [Google Scholar]
  24. Hussain MM. 24.  2000. A proposed model for the assembly of chylomicrons. Atherosclerosis 148:1–15 [Google Scholar]
  25. Hussain MM, Kancha RK, Zhou Z, Luchoomun J, Zu H, Bakillah A. 25.  1996. Chylomicron assembly and catabolism: role of apolipoproteins and receptors. Biochim. Biophys. Acta 1300:151–70 [Google Scholar]
  26. Hussain MM, Pan X. 26.  2009. Clock genes, intestinal transport and plasma lipid homeostasis. Trends Endocrinol. Metab. 20:177–85 [Google Scholar]
  27. Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. 27.  2012. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 9:14 [Google Scholar]
  28. Iqbal J, Anwar K, Hussain MM. 28.  2003. Multiple, independently regulated pathways of cholesterol transport across the intestinal epithelial cells. J. Biol. Chem. 278:31610–20 [Google Scholar]
  29. Iqbal J, Hussain MM. 29.  2009. Intestinal lipid absorption. Am. J. Physiol. Endocrinol. Metab. 296:E1183–94 [Google Scholar]
  30. Iqbal J, Li X, Chang BH, Chan L, Schwartz GJ. 30.  et al. 2010. An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption. J. Lipid Res. 51:1929–42 [Google Scholar]
  31. Jiang ZG, Liu Y, Hussain MM, Atkinson D, McKnight CJ. 31.  2008. Reconstituting initial events during the assembly of apolipoprotein B-containing lipoproteins in a cell-free system. J. Mol. Biol. 383:1181–94 [Google Scholar]
  32. Kalogeris TJ, Holden VR, Tso P. 32.  1999. Stimulation of jejunal synthesis of apolipoprotein A-IV by ileal lipid infusion is blocked by vagotomy. Am. J. Physiol. Gastrointest. Liver Physiol. 277:G1081–87 [Google Scholar]
  33. Konturek PC, Brzozowski T, Konturek SJ. 33.  2011. Gut clock: implication of circadian rhythms in the gastrointestinal tract. J. Physiol. Pharmacol. 62:139–50 [Google Scholar]
  34. Kumar NS, Mansbach CM II. 34.  1999. Prechylomicron transport vesicle: isolation and partial characterization. Am. J. Physiol. Gastrointest. Liver Physiol. 276:G378–86 [Google Scholar]
  35. LeSauter J, Hoque N, Weintraub M, Pfaff DW, Silver R. 35.  2009. Stomach ghrelin-secreting cells as food-entrainable circadian clocks. Proc. Natl. Acad. Sci. USA 106:13582–87 [Google Scholar]
  36. Levi F, Schibler U. 36.  2007. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47:593–628 [Google Scholar]
  37. Luchoomun J, Hussain MM. 37.  1999. Assembly and secretion of chylomicrons by differentiated Caco-2 cells: Nascent triglycerides and preformed phospholipids are preferentially used for lipoprotein assembly. J. Biol. Chem. 274:19565–72 [Google Scholar]
  38. Malloy JN, Paulose JK, Li Y, Cassone VM. 38.  2012. Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators. Am. J. Physiol. Gastrointest. Liver Physiol. 303:G461–73 [Google Scholar]
  39. Mansbach CM, Gorelick F. 39.  2007. Development and physiological regulation of intestinal lipid absorption. II. Dietary lipid absorption, complex lipid synthesis, and the intracellular packaging and secretion of chylomicrons. Am. J. Physiol. Gastrointest. Liver Physiol. 293:G645–50 [Google Scholar]
  40. Mansbach CM, Siddiqi SA. 40.  2010. The biogenesis of chylomicrons. Annu. Rev. Physiol. 72:315–33 [Google Scholar]
  41. Mendoza J. 41.  2007. Circadian clocks: setting time by food. J. Neuroendocrinol. 19:127–37 [Google Scholar]
  42. Morgan L, Arendt J, Owens D, Folkard S, Hampton S. 42.  et al. 1998. Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism. J. Endocrinol. 157:443–51 [Google Scholar]
  43. Mourad FH, Saade NE. 43.  2011. Neural regulation of intestinal nutrient absorption. Prog. Neurobiol. 95:149–62 [Google Scholar]
  44. Mu H, Hoy CE. 44.  2004. The digestion of dietary triacylglycerols. Prog. Lipid Res. 43:105–33 [Google Scholar]
  45. Neeli I, Siddiqi SA, Siddiqi S, Mahan J, Lagakos WS. 45.  et al. 2007. Liver fatty acid-binding protein initiates budding of pre-chylomicron transport vesicles from intestinal endoplasmic reticulum. J. Biol. Chem. 282:17974–84 [Google Scholar]
  46. Pacha J, Sumova A. 46.  2013. Circadian regulation of epithelial functions in the intestine. Acta Physiol. (Oxf.) 208:11–24 [Google Scholar]
  47. Pan X, Hussain MM. 47.  2007. Diurnal regulation of microsomal triglyceride transfer protein and plasma lipid levels. J. Biol. Chem. 282:24707–19 [Google Scholar]
  48. Pan X, Hussain MM. 48.  2009. Clock is important for food and circadian regulation of macronutrient absorption in mice. J. Lipid Res. 50:1800–13 [Google Scholar]
  49. Pan X, Hussain MM. 49.  2012. Gut triglyceride production. Biochim. Biophys. Acta 1821:727–35 [Google Scholar]
  50. Pan X, Jiang XC, Hussain MM. 50.  2013. Impaired cholesterol metabolism and enhanced atherosclerosis in Clock mutant mice. Circulation 128:1758–69 [Google Scholar]
  51. Pan X, Zhang Y, Wang L, Hussain MM. 51.  2010. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab. 12:174–86 [Google Scholar]
  52. Partch CL, Green CB, Takahashi JS. 52.  2014. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 24:90–99 [Google Scholar]
  53. Patton DF, Mistlberger RE. 53.  2013. Circadian adaptations to meal timing: neuroendocrine mechanisms. Front. Neurosci. 7:185 [Google Scholar]
  54. Phan CT, Tso P. 54.  2001. Intestinal lipid absorption and transport. Front. Biosci. 6:D299–319 [Google Scholar]
  55. Rey G, Reddy AB. 55.  2013. Connecting cellular metabolism to circadian clocks. Trends Cell Biol. 23:234–41 [Google Scholar]
  56. Scheving LA. 56.  2000. Biological clocks and the digestive system. Gastroenterology 119:536–49 [Google Scholar]
  57. Schlierf G, Dorow E. 57.  1973. Diurnal patterns of triglycerides, free fatty acids, blood sugar, and insulin during carbohydrate-induction in man and their modification by nocturnal suppression of lipolysis. J. Clin. Invest. 52:732–40 [Google Scholar]
  58. Schwartz GJ, Zeltser LM. 58.  2013. Functional organization of neuronal and humoral signals regulating feeding behavior. Annu. Rev. Nutr. 33:1–21 [Google Scholar]
  59. Siddiqi S, Saleem U, Abumrad NA, Davidson NO, Storch J. 59.  et al. 2010. A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER. J. Lipid Res. 51:1918–28 [Google Scholar]
  60. Siddiqi SA, Mahan J, Siddiqi S, Gorelick FS, Mansbach CM. 60.  2006. Vesicle-associated membrane protein 7 is expressed in intestinal ER. J. Cell Sci. 119:943–50 [Google Scholar]
  61. Siddiqi SA, Mansbach CM. 61.  2008. PKCζ-mediated phosphorylation controls budding of the pre-chylomicron transport vesicle. J. Cell Sci. 121:2327–38 [Google Scholar]
  62. Silver R, Balsam PD, Butler MP, LeSauter J. 62.  2011. Food anticipation depends on oscillators and memories in both body and brain. Physiol. Behav. 104:562–71 [Google Scholar]
  63. Sladek M, Rybova M, Jindrakova Z, Zemanova Z, Polidarova L. 63.  et al. 2007. Insight into the circadian clock within rat colonic epithelial cells. Gastroenterology 133:1240–49 [Google Scholar]
  64. Sotak M, Polidarova L, Musilkova J, Hock M, Sumova A, Pacha J. 64.  2011. Circadian regulation of electrolyte absorption in the rat colon. Am. J. Physiol. Gastrointest. Liver Physiol. 301:G1066–74 [Google Scholar]
  65. Stenvers DJ, Jonkers CF, Fliers E, Bisschop PH, Kalsbeek A. 65.  2012. Nutrition and the circadian timing system. Prog. Brain Res. 199:359–76 [Google Scholar]
  66. Stephan FK. 66.  2002. The “other” circadian system: food as a zeitgeber. J. Biol. Rhythms 17:284–92 [Google Scholar]
  67. Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. 67.  2001. Entrainment of the circadian clock in the liver by feeding. Science 291:490–93 [Google Scholar]
  68. Storch J, Thumser AE. 68.  2010. Tissue-specific functions in the fatty acid-binding protein family. J. Biol. Chem. 285:32679–83 [Google Scholar]
  69. Tavakkolizadeh A, Ramsanahie A, Levitsky LL, Zinner MJ, Whang EE. 69.  et al. 2005. Differential role of vagus nerve in maintaining diurnal gene expression rhythms in the proximal small intestine. J. Surg. Res. 129:73–78 [Google Scholar]
  70. Vener KJ, Szabo S, Moore JG. 70.  1989. The effect of shift work on gastrointestinal (GI) function: a review. Chronobiologia 16:421–39 [Google Scholar]
  71. Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL. 71.  et al. 1994. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264:719–25 [Google Scholar]
  72. Welsh DK, Takahashi JS, Kay SA. 72.  2010. Suprachiasmatic nucleus: cell autonomy and network properties. Annu. Rev. Physiol. 72:551–77 [Google Scholar]
  73. Williams KJ. 73.  2008. Molecular processes that handle—and mishandle—dietary lipids. J. Clin. Invest. 118:3247–59 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error