MicroRNA-370 controls the expression of microRNA-122 and Cpt1alpha and affects lipid metabolism.
We previously observed that treatment of mice with a dominant negative form of cJun (dn-cJun) increased the expression of genes involved in lipid metabolism and modulated the expression of nine microRNAs (miR). To investigate the potential effect of these miRs on the expression of the genes of lipid metabolism, we performed studies in cultured HepG2 cells. Transfection of HepG2 cells with sense or antisense miR-370 or miR-122 upregulated and downregulated, respectively, the transcription factor sterol-regulatory element binding protein 1c (SREBP-1c) and the enzymes diacylglycerol acyltransferase-2 (DGAT2), fatty acid synthase (FAS), and acyl-CoA carboxylase 1 (ACC1) that regulate fatty acid and triglyceride biosynthesis. The other seven miRs identified by the miR array screening did not affect the expression of lipogenic genes. miR-370 upregulated the expression of miR-122. Furthermore, the effect of miR-370 on the expression of the lipogenic genes was abolished by antisense miR-122. miR-370 targets the 3' untranslated region (UTR) of Cpt1alpha, and it downregulated the expression of the carnitine palmitoyl transferase 1alpha (Cpt1alpha) gene as well as the rate of beta oxidation. Our data suggest that miR-370 acting via miR-122 may have a causative role in the accumulation of hepatic triglycerides by modulating initially the expression of SREBP-1c, DGAT2, and Cpt1alpha and, subsequently, the expression of other genes that affect lipid metabolism.
Iliopoulos
Dimitrios
D
Department of Biological Chemistry and Molecular Pharmacology, School of Medicine, Harvard University, Boston, MA, USA.
Drosatos
Konstantinos
K
Hiyama
Yaeko
Y
Goldberg
Ira J
IJ
Zannis
Vassilis I
VI
D020413:3' Untranslated Regions / Q000235:genetics; D000123:Acetyltransferases / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005110:Extracellular Space / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D016758:Genes, jun / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D019014:fas Receptor / Q000235:genetics
D020413:3' Untranslated Regions; C491899:Fas protein, mouse; D005227:Fatty Acids; C551449:MIRN370 microRNA, mouse; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D019014:fas Receptor; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase