In liver, ABCA1 is essential for the production of the precursor forms of high-density lipoprotein (HDL)

In liver, ABCA1 is essential for the production of the precursor forms of high-density lipoprotein (HDL). of cholesterol, whereas preferentially activates the synthesis of fatty acids (4). Najafi -Shoushtari and Rayner reveal that both genes also encode, within their introns, a microRNA (blocks the egress of cholesterol from cells by reducing the mRNA and protein levels for ABCA1, a transporter in the plasma membrane that secretes cholesterol from cells (5). When cells are depleted of cholesterol, both the transcription of rise modestly. and encode and isoforms target for destruction several mRNAsmost prominently the mRNA encoding ABCA1 that contain a highly conserved target sequence in their 3-untranslated regions. When cultured Vegfa mammalian cells were transfected with levels. ABCA1 functions most prominently in macrophages and hepatocytes (5). In macrophages, it excretes cholesterol that accumulates as a result of the uptake of oxidized cholesterol-carrying lipoproteins. In liver, ABCA1 is essential for the production of the precursor forms of high-density lipoprotein (HDL). Indeed, Najafi -Shoushtari and Rayner show that delivery of a antagonist leads to a small but significant increase in plasma HDL. So far, the most remarkable feature of the story is the pattern of evolutionary conservation. The precursor for mature is found within the same intron of from many animal species, including large and small mammals, chickens, and frogs. There is even a perfectly conserved mature form of in the single gene controls fatty acid production (6). Moreover, the fruit fly genome does not contain in is unknown. In contrast to the uniform conservation of in in (according to the U.S. National Center for Biotechnology BMS-582949 Information database). The genes from large mammals encode in the genes of small mammals (rats and mice) or chickens. Although the amount of mature rises and falls in concert with mRNA, the amplitude of BMS-582949 variation is quite small in BMS-582949 the systems studied by Najafi-Shoushtari and Rayner This is likely because variations in cellular cholesterol levels cause relatively minor changes in the transcription of BMS-582949 the genes. Cholesterol regulates SREBP activity most profoundly at the level of protein processing (3). SREBPs are synthesized as membrane proteins in the endoplasmic reticulum and transported to the Golgi complex, where they are proteolyzed to release active fragments that enter the nucleus. There, they enhance transcription of cholesterol-synthesizing genes, such as those encoding 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase. When cells are depleted of cholesterol, the level of nuclear SREBP-2 increases by orders of magnitude owing to increased proteolytic processing, and mRNAs encoding HMG CoA synthase and reductase increase correspondingly (4). By contrast, the mRNA encoding SREBP-2 increases by less than a factor of 2, explaining why also shows relatively small changes. Whether or not such small changes influence plasma HDL in humans is yet to be determined. One circumstance in which transcription of an gene is profoundly regulated in vivo and where changes in are likely to be important clinically is in the liver (see the figure). Hepatocytes produce two alternatively spliced transcripts of and differ from those of in liver is enhanced by insulin, working in concert with nuclear liver X receptors (8, 9). When insulin levels are high, is transcribed at extremely high levels, and the resultant nuclear SREBP-1c activates genes necessary to produce.