Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation.
The regulation of synthesis, degradation, and distribution of lipids is crucial for homeostasis of organisms and cells. The sterol regulatory element-binding protein (SREBP) transcription factor family is post-translationally activated in situations of reduced lipid abundance and activates numerous genes involved in cholesterol, fatty acid, and phospholipid synthesis. In this study, we provide evidence that the primary transcript of SREBP2 contains an intronic miRNA (miR-33) that reduces cellular cholesterol export via inhibition of translation of the cholesterol export pump ABCA1. Notably, miR-33 also inhibits translation of several transcripts encoding proteins involved in fatty acid β-oxidation including CPT1A, HADHB, and CROT, thereby reducing fatty acid degradation. The genetic locus encoding SREBP2 and miR-33 therefore contains a protein that increases lipid synthesis and a miRNA that prevents export and degradation of newly synthesized lipids. These results add an additional layer of complexity to our understanding of lipid homeostasis and might open possibilities for future therapeutic intervention.
Gerin
Isabelle
I
Laboratory for Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, 1200 Bruxelles, Belgium.
Clerbaux
Laure-Alix
LA
Haumont
Olivier
O
Lanthier
Nicolas
N
Das
Arun K
AK
Burant
Charles F
CF
Leclercq
Isabelle A
IA
MacDougald
Ormond A
OA
Bommer
Guido T
GT
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis*; D010743:Phospholipids / Q000737:chemistry; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*
D005227:Fatty Acids; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D010743:Phospholipids; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol