Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus

Abstract

The sterol regulatory element-binding factor-2 (SREBF2) gene is a bifunctional locus encoding SREBP-2, a well-known transcriptional regulator of genes involved in cholesterol biosynthesis, and microRNA-33a, which has recently been shown to reduce expression of proteins involved in export of cholesterol and β-oxidation of fatty acids, thus adding an unexpected layer of complexity and fine-tuning to regulation of lipid homeostasis.

Figure 1. miR-33a collaborates with SREBP-2 to maintain cellular lipid homeostasis

(A) Traditional model of SREBP-2 function. SREBP-2 contains two transmembrane domains and is inserted in the membrane of the endoplasmic reticulum (ER). Under conditions of abundant cholesterol (or phosphatidylethanolamine), SREBP2 is retained in the ER by a complex of SCAP and INSIG proteins. When cholesterol levels fall, the interaction between INSIG and SCAP is disrupted, allowing SCAP to interact with COPII-coated vesicles and target SREBP-2 for export to the Golgi apparatus. Here, in two consecutive cleavages by S1P and S2P, a transcriptionally competent N-terminal fragment is released. After translocation to the nucleus, SREBP-2 induces expression of genes involved in cholesterol and fatty acid synthesis, which serve to normalize cellular lipid levels (modified from (Ikonen, 2008)). (B) Integrated model for how the bifunctional SREBF2 locus maintains lipid homeostasis. After processing from an intron of SREBF2, miR-33a reduces cellular cholesterol export by inhibiting expression of ABCA1 (and in the mouse ABCG1). In addition, miR-33a reduces mitochondrial fatty acid β-oxidation via inhibition of HADHB, CROT and CPT1A to increase intracellular lipid levels. Thus the SREBF2 locus uses two distinct mechanisms to maintain lipid homeostasis: regulated transcriptional activity of SREBP-2 and translational repression by miR-33a.

Figure 2. Influence of miR-33a on HDL cholesterol levels

miR-33a is generated from an intron of the SREBF2 primary transcript and inhibits translation of ABCA1 and ABCG1 mRNAs, and perhaps NPC1. Putative flux of cholesterol is denoted with red arrows under conditions of A) low sterol concentrations (A) or high sterol concentrations/miR-33a deficiency (B). De novo HDL synthesis requires ABCA1-dependent cholesterol secretion from the liver and intestine into nascent HDL particles. In peripheral organs, HDL-particles accept cholesterol from ABCA1 and ABCG1 transporters. Hepatic uptake of HDL particles via the scavenger receptor-B1 (SR-B1) completes the process of reverse cholesterol transport. To deliver fatty acids and cholesterol to peripheral organs, the liver synthesizes VLDL particles. Delivery of fatty acids and cholesterol eventually leads to the transformation of VLDL into LDL particles, which are cleared from circulation via hepatic LDL receptor (LDLR). Oxidation and/or impaired clearance of LDL increase risk of foam cell formation and atheroma formation. Upon reduction of hepatic cholesterol levels, SREBP-2 increases transcription of genes involved in cholesterol synthesis (e.g. β-HMG CoA reductase), as well as LDLR to increase uptake of LDL. (A) Low sterol concentraions promote the expression of miR-33a, which inhibits the expression of ABCA1 and ABCG1 to suppress cholesterol export from liver, intestine and macrophages and thereby prevents further decreases in intercellular sterol concentrations. miR-33a may also influence intercellular cholesterol distribution by inhibiting NPC1 expression. (B) Suppression of miR-33a expression by either high sterol concentrations or experimental intervention results in increased ABCA1 and ABCG1 expression, which potentially increases not only de novo synthesis of HDL particles but also loading with cholesterol in the periphery. For simplicicty, we did not include a schematic representation of SREBP-2 expression in peripheral tissues, and do not show effects of cholesterol synthesis and cholesterol secretion.