Dietary oleanolic acid mediates circadian clock gene expression in liver independently of diet and animal model but requires apolipoprotein A1.
Oleanolic acid is a triterpene widely distributed throughout the plant kingdom and present in virgin olive oil at a concentration of 57 mg/kg. To test the hypotheses that its long-term administration could modify hepatic gene expression in several animal models and that this could be influenced by the presence of APOA1-containing high-density lipoproteins (HDLs), diets including 0.01% oleanolic acid were provided to Apoe- and Apoa1-deficient mice and F344 rats. Hepatic transcriptome was analyzed in Apoe-deficient mice fed long-term semipurified Western diets differing in the oleanolic acid content. Gene expression changes, confirmed by reverse transcriptase quantitative polymerase chain reaction, were sought for their implication in hepatic steatosis. To establish the effect of oleanolic acid independently of diet and animal model, male rats were fed chow diet with or without oleanolic acid, and to test the influence of HDL, Apoa1-deficient mice consuming the latter diet were used. In Apoe-deficient mice, oleanolic acid intake increased hepatic area occupied by lipid droplets with no change in oxidative stress. Bmal1 and the other core component of the circadian clock, Clock, together with Elovl3, Tubb2a and Cldn1 expressions, were significantly increased, while Amy2a5, Usp2, Per3 and Thrsp were significantly decreased in mice receiving the compound. Bmal1 and Cldn1 expressions were positively associated with lipid droplets. Increased Clock and Bmal1 expressions were also observed in rats, but not in Apoa1-deficient mice. The core liver clock components Clock-Bmal1 are a target of oleanolic acid in two animal models independently of the diets provided, and this compound requires APOA1-HDL for its hepatic action.
Departamento Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
Clara
C
Gabás-Rivera
Roberto
R
Martínez-Beamonte
José L
JL
Ríos
María A
MA
Navarro
Joaquín C
JC
Surra
Carmen
C
Arnal
María J
MJ
Rodríguez-Yoldi
Jesús
J
Osada
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D057906:Circadian Clocks / Q000235:genetics*; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D000081031:Fatty Acid Elongases; D015870:Gene Expression; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000494:pharmacology*; D000069463:Olive Oil; D018384:Oxidative Stress / Q000187:drug effects; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D010938:Plant Oils / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C538961:Bmal1 protein, mouse; D008076:Cholesterol, HDL; D062445:Claudin-1; C568113:Cldn1 protein, mouse; C000630953:ELOVL3 protein, human; C000630960:Elovl3 protein, mouse; D009687:Nuclear Proteins; D000069463:Olive Oil; C512645:Per3 protein, mouse; D056950:Period Circadian Proteins; D010938:Plant Oils; D012333:RNA, Messenger; C501477:Thrsp protein, mouse; D014157:Transcription Factors; D009828:Oleanolic Acid; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse
Apolipoprotein E-deficient mice; BSTFA; Bmal1; Clock; IPA; Ingenuity Pathway Analysis; N,O-bis-(trimethylsilyl)trifluoroacetamide; OA; Oleanolic acid; Olive oil; PCR; RT; oleanolic acid; polymerase chain reaction; reverse transcriptase