The Role of Hepatic Liver X Receptor α-and Sterol Regulatory Element Binding Protein-1c-Mediated Lipid Disorder in the Pathogenesis of Non-Alcoholic Steatohepatitis in Rats
Free accessResearch articleFirst published online August, 2011
The Role of Hepatic Liver X Receptor α-and Sterol Regulatory Element Binding Protein-1c-Mediated Lipid Disorder in the Pathogenesis of Non-Alcoholic Steatohepatitis in Rats
Liver X receptor α (LXRα) and sterol regulatory element binding protein-1c (SREBP-1c) were studied in rats with non-alcoholic steatohepatitis (NASH) induced by a high-fat diet. Forty 5-week-old rats were fed either a high-fat diet (n = 30) or a normal diet (n = 10) for 9, 13 or 17 weeks. The mRNA and protein levels for LXRα and SREBP-1c were measured at each time point, as was fatty acid synthase (FAS) activity and the serum levels of free fatty acid (FFA) and triglyceride (TG). The mRNA and protein levels for LXRα and SREBP-1c, FAS activity and serum levels of FFA and TG all significantly increased from week 9 in the high-fat diet rats versus controls. In conclusion, a high-fat diet upregulates LXRα which, in turn, upregulates SREBP-1c, increasing the activity of FAS and FFA and accumulation of TG in hepatocytes. Thus, LXRα and SREBP-1c contribute to the development of NASH.
FanJGZhuJLiXJ: Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol2005; 43: 508–514.
2.
StethSGGordonFDChoopraS: Nonalcoholic steatohepatitis. Ann Intern Med1997; 126: 137–145.
3.
FassioEAlvarezEDomínguezN: Natural history of nonalcoholic steatohepatitis: A longitudinal study of repeat liver biopsies. Hepatology2004; 40: 820–826.
4.
BruntEMJanneyCGDi BisceglieAM: Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am J Gastroenterol1999; 94: 2467–2474.
5.
OngJPYounossiZM: Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis2007, 11: 1–16.
McClainCJMokshagundamSPBarveSS: Mechanisms of non-alcoholic steatohepatitis. Alcohol2004; 34: 67–79.
12.
KameiYMiuraSSuganamiT: Regulation of SREBP1c gene expression in skeletal muscle: role of retinoid X receptor/liver X receptor and forkhead-O1 transcription factor. Endocrinology2008; 149: 2293–2305.
13.
Amemiya-KudoMShimanoHYoshikawaT: Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J Biol Chem2000; 275: 31078–31085.
EdwardsPATaborDKastHR: Regulation of gene expression by SREBP and SCAP. Biochim Biophys Acta2000; 1529: 103–113.
16.
DentinRGirardJPosticC: Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie2005; 87: 81–86.
17.
TakeuchiYYahagiNNakagawaY: In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-1c expression. Biochem Biophys Res Commun2007; 363: 329–335.
18.
ChenGLiangGOuJ: Central role for liver X receptor in insulin-mediated activation of SREBP-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci U S A2004; 101: 11245–11250.
19.
YoshikawaTIdeTShimanoH: Cross-talk between peroxisome proliferator-activated receptor (PPAR) 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 Endocrinol2003; 17: 1240–1254.
20.
CastrilloAJosephSBVaidyaSA: Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell2003; 12: 805–816.
21.
KhanSAVanden HeuvelJP: Role of nuclear receptors in the regulation of gene expression by dietary fatty acids (review). J Nutr Biochem2003; 14: 554–567.
22.
PeetDJJanowskiBAMangelsdorfDJ: The LXRs: A new class of oxysterol receptors. Curr Opin Genet Dev1998; 8: 571–575.
23.
SakamotoAKawasakiTKazawaT: Expression of liver X receptor α in rat fetal tissues at different developmental stages. J Histochem Cytochem2007; 55: 641–649.
24.
DuplusEForestC: Is there a single mechanism for fatty acid regulation of gene transcripition?Biochem Pharmacol2003; 64: 893–901.
25.
ZhangHShiZLiuY: Lipid homeostasis and oxidative stress in the liver of male rats exposed to perfluorododecanoic acid. Toxicol Appl Pharmacol2008; 227: 16–25.
26.
GentileCLPagliassottiMJ: The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem2008; 19: 567–576.
27.
KleinerDEBruntEMVan NattaM: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology2005; 41: 1313–1321.
28.
HsuRYYunSL: Stabilization and physicochemical properties of the fatty acid synthetase of chicken liver. Biochemistry1970; 9: 239–245.
29.
TianWXHsuRYWangYS: Studies on the reactivity of the essential sulfhydryl groups as a conformational probe for the fatty acid synthetase of chicken liver. Inactivation by 5,5′-dithiobis-(2-nitrobenzoic acid) and intersubunit cross-linking of the inactivated enzyme. J Biol Chem1985; 260: 11375–11387.
30.
ChitturiSFarrellGC: Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis2001; 21: 27–41.
31.
LiewPLLeeWJLeeYC: Hepatic histopathology of morbid obesity: concurrence of other forms of chronic liver disease. Obes Surg2006; 16: 1584–1593.
32.
PortincasaPGrattaglianoIPalmieriVO: Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management. Clin Biochem2005; 38: 203–217.
33.
GeorgeJLiddleC: Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets. Mol Pharm2008; 5: 49–59.
34.
JulianoRADeckelbaumRJWorgallTS: Fatty acids, cholesterol, and sphingolipids: interactive regulators and targets for SREBP processing. International Congress Series2004; 1262: 55–58.
CrisafulliCDi PaolaRMazzonE: Liver X receptor agonist treatment reduced splanchnic ischemia and reperfusion injury. J Leukoc Biol2010; 87: 309–321.
40.
ShulmanAIMangelsdorfDJ: Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med2005; 353: 604–615.
41.
SzantoANarkarVShenQ: Retinoid X receptors: X-ploring their (patho)physiological functions. Cell Death Differ2004; 11 (suppl 2): S126–S143.
42.
MuscatGEWagnerBLHouJ: Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors. J Biol Chem2002; 277: 40722–40728.
43.
NakataniTKatsumataAMiuraS: Effects of fish oil feeding and fasting on LXRα/RXRα binding to LXRE in the SREBP-1c promoter in mouse liver. Biochim Biophys Acta2005; 1736: 77–86.
44.
HortonJDGoldsteinJLBrownMS: SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest2002; 109: 1125–1131.
45.
DengXYellaturuCCagenL: Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1). J Biol Chem2007; 282: 17517–17529.
46.
YoshikawaTShimanoHAmemiya-KudoM: Identification of liver X receptor—retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol2001; 21: 2991–3000.
47.
PawarABotolinDMangelsdorfDJ: The role of liver X receptor-α in the fatty acid regulation of hepatic gene expression. J Biol Chem2003; 278: 40736–40743.
48.
TöröcsikDSzantoANagyL: Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages. Mol Aspects Med2009, 30: 134–152.
49.
MarraFGastaldelliABaroniG Svegliati: Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med2008; 14: 72–81.
