Skip to main content
Log in

High-Fat Diets and LXRs Expression in Rat Liver and Hypothalamus

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Disturbances on lipid metabolism are associated with health disorders. High-fat diets (HFDs) consumption promotes cardiovascular and neurodegenerative diseases where cholesterol plays an important role. Among regulators of this steroid homeostasis, the liver X receptors (LXRs) induce genes that protect cells from cholesterol overload. We previously described how both hypothalamic LXRα and LXRβ are sensitive to a high-fructose diet, suggesting that these receptors trigger responses related to control of energy and food intake. The present work’s main objective was to study the effect of different HFDs on LXRs expression (in hypothalamus and liver), and lipid profile. Male rats received control diet (CD), HFD1 (CD + bovine fat (BF)), HFD2 (CD + BF + cholic acid (CA)), HFD3 (CD + BF + cholesterol), or HFD4 (CD + BF + CA + cholesterol) for different time periods. Hypothalamic LXRβ, both hepatic LXRs subtypes, and total cholesterol (TC) raised after 2 weeks of HFDs. Four and 8 weeks of HFD3 and HFD4 increased the LXRs subtypes in both tissues and TC levels. Only HFD4 reduced triglycerides (TG) levels after 2 and 8 weeks. The TC and TG values correlated significantly with LXRs expression only in rats fed with HFD4. These data add relevant information about how diet composition can produce different scales of hypercholesterolemia states accompanied with central and peripheral changes in the LXRs expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Bantubungi K, Prawitt J, Staels B (2012) Control of metabolism by nutrient-regulated nuclear receptors acting in the brain. J Steroid Biochem Mol Biol 130:126–137

    CAS  PubMed  Google Scholar 

  • Baranowski M (2008) Biological role of liver X receptors. J Physiol Pharmacol 59:31–55

    PubMed  Google Scholar 

  • Beigneux A, Hofmann AF, Young SG (2002) Human CYP7A1 deficiency: progress and enigmas. J Clin Invest 110:29–31

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blain JF, Poirier J (2004) Cholesterol homeostasis and the pathophysiology of Alzheimer’s disease. Expert Rev Neurother 4:823–829

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    CAS  Google Scholar 

  • Cai D (2012) One step from prediabetes to diabetes: hypothalamic inflammation? Endocrinology 153:1010–1013

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cao G, Liang Y, Jiang XC, Eacho PI (2004) Liver X receptors as potential therapeutic targets for multiple diseases. Drug News Perspect 17:35–41

    CAS  PubMed  Google Scholar 

  • Carey MC, Mazer NA (1984) Biliary lipid secretion in health and in cholesterol gallstone disease. Hepatology 4(5):31S–37S

    CAS  PubMed  Google Scholar 

  • Cave MC, Clair HB, Hardesty JE, Falkner KC, Feng W, Clark BJ, Sidey J, Shi H, Aqel BA, McClain CJ, Prough RA (2016) Nuclear receptors and nonalcoholic fatty liver disease. Biochim Biophys Acta 1859:1083–1099

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cha JY, Repa JJ (2007) The liver X receptor (LXR) and hepatic lipogenesis—the carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem 282(1):743–751

    CAS  PubMed  Google Scholar 

  • Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H, Gores G (2011) Fast food diet mouse: novel small animal model of nash with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 301:G825–G834

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coirini H, Marusic ET, De Nicola AF, Rainbow TC, McEwen BS (1983) Identification of mineralocorticoid binding sites in rat brain by competition studies and density gradient centrifugation. Neuroendocrinology 37:354–360

    CAS  PubMed  Google Scholar 

  • Côté I, Ngo Sock ET, Lévy É, 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

    PubMed  Google Scholar 

  • Cullen P (2000) Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 86:943–949

    CAS  PubMed  Google Scholar 

  • Dai YB, Tan XJ, Wu WF, Warner M, Gustafsson JÅ (2012) Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease. Proc Natl Acad Sci USA 109:13112–13117

    CAS  PubMed  Google Scholar 

  • Dalvi PS, Chalmers JA, Luo V, Han DY, Wellhauser L, Liu Y, Tran DQ, Castel J, Luquet S, Wheeler MB, Belsham DD (2017) High fat induces acute and chronic inflammation in thehypothalamus: effect of high-fat diet, palmitate and TNF-alpha on appetite-regulating NPY neurons. Int J Obes 41:149–158

    CAS  Google Scholar 

  • De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199

    PubMed  Google Scholar 

  • Fan X, Kim HJ, Bouton D, Warner M, Gustafsson JA (2008) Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons. Proc Natl Acad Sci USA 105:13445–13450

    CAS  PubMed  Google Scholar 

  • Fidèle N, Joseph B, Emmanuel T, Théophile D (2017) Hypolipidemic, antioxidant and anti-atherosclerogenic effect of aqueous extract leaves of Cassia occidentalis Linn (Caesalpiniaceae) in diet-induced hypercholesterolemic rats. BMC Complement Altern Med 17(1):76. https://doi.org/10.1186/s12906-017-1566-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franciosi S, Gama Sosa MA, English DF, Oler E, Oung T, Janssen WG, De Gasperi R, Schmeidler J, Dickstein DL, Schmitz C, Gandy S, Hof PR, Buxbaum JD, Elder GA (2009) Novel cerebrovascular pathology in mice fed a high cholesterol diet. Mol Neurodegener 4:42

    PubMed  PubMed Central  Google Scholar 

  • Frayn KN (2002) Adipose tissue as a buffer for daily lipid flux. Diabetologia 45(9):1201–1210

    CAS  PubMed  Google Scholar 

  • Gao Q, Horvath TL (2008) Neuronal control of energy homeostasis. FEBS Lett 582:132–141

    CAS  PubMed  Google Scholar 

  • Ghibaudi L, Cook J, Farley C, van Heek M, Hwa JJ (2002) Fat intake affects adiposity, comorbidity factors, and energy metabolism of Sprague-Dawley rats. Obes Res 10:956–963

    CAS  PubMed  Google Scholar 

  • Gupta S, Pandak WM, Hylemon PB (2002) LXR alpha is the dominant regulator of CYP7A1 transcription. Biochem Biophys Res Commun 293:338–343

    CAS  PubMed  Google Scholar 

  • Horvath TL, Sarman B, Garcia-Caceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, Tschöp MH (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA 107:14875–14880

    CAS  PubMed  Google Scholar 

  • Hwang IK, Kim IY, Kim DW, Yoo KY, Kim YN, Yi SS, Won MH, Lee IS, Yoon YS, Seong JK (2008) Strain-specific differences in cell proliferation and differentiation in the dentate gyrus of C57BL/6N and C3H/HeN mice fed a high fat diet. Brain Res 1241:1–6

    CAS  PubMed  Google Scholar 

  • Karnani M, Burdakov D (2011) Multiple hypothalamic circuits sense and regulate glucose levels. Am J Physiol Regul Integr Comp Physiol 300:R47–R55

    CAS  PubMed  Google Scholar 

  • Kast HR, Nguyen CM, Sinal CJ, Jones SA, Laffitte BA, Reue K, Gonzalez FJ, Willson TM, Edwards PA (2001) Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 15:1720–1728

    CAS  PubMed  Google Scholar 

  • Kim HJ, Fan X, Gabbi C, Yakimchuk K, Parini P, Warner M, Gustafsson JA (2008) Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson’s dementia. Proc Natl Acad Sci USA 105:2094–2099

    CAS  PubMed  Google Scholar 

  • Koch S, Donarski N, Goetze K, Kreckel M, Stuerenburg HJ, Buhmann C, Beisiegel U (2001) Characterization of four lipoprotein classes in human cerebrospinal fluid. J Lipid Res 42:1143–1151

    CAS  PubMed  Google Scholar 

  • Kruse MS, Rey M, Vega MC, Coirini H (2012) Alterations of LXRα and LXRβ in the hypothalamus of glucose-intolerant rats. J Endocrinol 215:51–58

    CAS  PubMed  Google Scholar 

  • Kruse MS, Suarez LG, Coirini H (2017) Regulation of the expression of LXR in rat hypothalamic and hippocampal explants. Neurosci Lett 639:53–58

    CAS  PubMed  Google Scholar 

  • Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L (2005) Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11:320–327

    CAS  PubMed  Google Scholar 

  • Laurencikiene J, Rydén M (2012) Liver X receptors and fat cell metabolism. Int J Obes (Lond) 36:1494–1502

    CAS  Google Scholar 

  • Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515

    CAS  PubMed  Google Scholar 

  • Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, Yokoyama M, Honda M, Zen Y, Nakanuma Y, Miyamoto K, Kaneko S (2007) Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 46(5):1392–1403

    CAS  PubMed  Google Scholar 

  • Mohammadi A, Oshaghi EA (2014) Effect of garlic on lipid profile and expression of LXR alpha in intestine and liver of hypercholesterolemic mice. J Diabetes Metab Disord 13(1):20

    PubMed  PubMed Central  Google Scholar 

  • Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN, Uranga RM, Bruce-Keller AJ, Keller JN (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased nrf2 signaling. J Neurochem 114:1581–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443:289–295

    CAS  PubMed  Google Scholar 

  • Nishina PM, Verstuyft J, Paigen B (1990) Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J Lipid Res 31:859–869

    CAS  PubMed  Google Scholar 

  • Panchal SK, Brown L (2011) Rodent models for metabolic syndrome research. J Biomed Biotechnol 2011:351982. https://doi.org/10.1155/2011/351982

    Article  PubMed  Google Scholar 

  • Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693–704

    CAS  PubMed  Google Scholar 

  • Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B (2003) Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17:259–272

    PubMed  Google Scholar 

  • Pullinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, Verhagen A, Rivera CR, Mulvihill SJ, Malloy MJ, Kane JP (2002) Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110:109–117

    CAS  PubMed  PubMed Central  Google Scholar 

  • Repa JJ, Mangelsdorf DJ (2000) The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 16:459–481

    CAS  PubMed  Google Scholar 

  • Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14:2819–2830

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rey M, Kruse MS, Alvarez LD, Ghini AA, Veleiro AS, Burton G, Coirini H (2013) Neuroprotective action of synthetic steroids with oxygen bridge. Activity on GABAA receptor. Exp Neurol 249:49–58

    CAS  PubMed  Google Scholar 

  • Riccioni G, Sblendorio V (2012) Atherosclerosis: from biology to pharmacological treatment. J. Geriatr Cardiol 9:305–317

    PubMed  PubMed Central  Google Scholar 

  • Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72:137–174

    CAS  PubMed  Google Scholar 

  • Shanmugasundaram KR, Visvanathan A, Dhandapani K, Srinivasan N, Rasappan P, Gilbert R, Alladi S, Kancharla S, Vasanthi N (1986) Effect of high-fat diet on cholesterol distribution in plasma lipoproteins, cholesterol esterifying activity in leucocytes, and erythrocyte membrane components studied: importance of body weight. Am J Clin Nutr 44:805–815

    CAS  PubMed  Google Scholar 

  • Sparks DL, Liu H, Scheff SW, Coyne CM, Hunsaker JC (1993) Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals. J Neuropathol Exp Neurol 52:135–142

    CAS  PubMed  Google Scholar 

  • Srivastava RA, Srivastava N, Averna M (2000) Dietary cholic acid lowers plasma levels of mouse and human apolipoprotein A-I primarily via a transcriptional mechanism. Eur J Biochem 267:4272–4280

    CAS  PubMed  Google Scholar 

  • Stark AH, Timar B, Madar Z (2000) Adaptation of Sprague Dawley rats to long-term feeding of high fat or high fructose diets. Eur J Nutr 39:229–234

    CAS  PubMed  Google Scholar 

  • Steffensen KR, Nilsson M, Schuster GU, Stulnig TM, Dahlman-Wright K, Gustafsson JA (2003) Gene expression profiling in adipose tissue indicates different transcriptional mechanisms of liver X receptors alpha and beta, respectively. Biochem Biophys Res Commun 310:589–593

    CAS  PubMed  Google Scholar 

  • Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschöp MH, Schwartz MW (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153–162

    CAS  PubMed  Google Scholar 

  • Thornton SJ, Wong E, Lee SD, Wasan KM (2008) Effect of dietary fat on hepatic liver X receptor expression in P-glycoprotein deficient mice: implications for cholesterol metabolism. Lipids Health Dis 7:21

    PubMed  PubMed Central  Google Scholar 

  • Treiber-Held S, Distl R, Meske V, Albert F, Ohm TG (2003) Spatial and temporal distribution of intracellular free cholesterol in brains of a Niemann-Pick type C mouse model showing hyperphosphorylated tau protein. Implications for Alzheimer’s disease. J Pathol 200:95–103

    CAS  PubMed  Google Scholar 

  • Ulven SM, Dalen KT, Gustafsson JA, Nebb HI (2005) LXR is crucial in lipid metabolism. Prostaglandins Leukot Essent Fatty Acids 73:59–63

    CAS  PubMed  Google Scholar 

  • Valdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR, Bennett ML, Gerritse I, Fasnacht R, Barres BA, Thaler JP, Koliwad SK (2017) Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab 26:185–197.e3

    CAS  PubMed  PubMed Central  Google Scholar 

  • Van Herck MA, Vonghia L, Francque SM (2017) Animal models of nonalcoholic fatty liver disease—a Starter’s guide. Nutrients 9(10):E1072. https://doi.org/10.3390/nu9101072

    Article  CAS  PubMed  Google Scholar 

  • Waise TMZ, Toshinai K, Naznin F, NamKoong C, Md Moin AS, Sakoda H, Nakazato M (2015) One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice. Biochem Biophys Res Commun 464:1157–1162

    CAS  PubMed  Google Scholar 

  • Wang H, Chen J, Hollister K, Sowers LC, Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3(5):543–553

    CAS  PubMed  Google Scholar 

  • Wang YM, Zhang B, Xue Y, Li ZJ, Wang JF, Xue CH, Yanagita T (2010) The mechanism of dietary cholesterol effects on lipids metabolism in rats. Lipids Health Dis 9:4

    PubMed  PubMed Central  Google Scholar 

  • Whitney KD, Watson MA, Collins JL, Benson WG, Stone TM, Numerick MJ, Tippin TK, Wilson JG, Winegar DA, Kliewer SA (2002) Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Mol Endocrinol 16:1378–1385

    CAS  PubMed  Google Scholar 

  • Xu G, Pan LX, Li H, Shang Q, Honda A, Shefer S, Bollineni J, Matsuzaki Y, Tint GS, Salen G (2004) Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated. Am J Physiol Gastrointest Liver Physiol 286:G730–G735

    CAS  PubMed  Google Scholar 

  • Yoshikawa T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Nakakuki M, Yatoh S, Iizuka Y, Tomita S, Ohashi K, Takahashi A, Sone H, Gotoda T, Osuga J, Ishibashi S, Yamada N (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) a and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol Endocrinol 17:1240–1254

    CAS  PubMed  Google Scholar 

  • Zelcer N, Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116(3):607–614

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Zhang X, Chen X, Sun Y, Dai Y, Chen C, Zhang T, Yan Z (2017) Studies on the regulation of lipid metabolism and the mechanism of the aqueous and ethanol extracts of Usnea. Biomed Pharmacother 94:930–936

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET; Grants Nos. PIP-860 and PIP-243). MR and RNM-H were, respectively, supported by postdoctoral and doctoral fellowships from CONICET.

Author information

Authors and Affiliations

Authors

Contributions

The authors’ responsibilities were as follow: MR and HC designed and conducted the research, had primary responsibility for the final content, and wrote the paper with contribution by coauthors; MR, MSK, and RNM-H performed the TC and TG analysis and the Western blot studies; MR statistically analyzed the data; and all authors read and approved the final manuscript.

Corresponding author

Correspondence to Héctor Coirini.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rey, M., Kruse, M.S., Magrini-Huamán, R.N. et al. High-Fat Diets and LXRs Expression in Rat Liver and Hypothalamus. Cell Mol Neurobiol 39, 963–974 (2019). https://doi.org/10.1007/s10571-019-00692-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-019-00692-6

Keywords

Navigation