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The two fundamental lipid molecules in animals are cholesterol and fatty acids. Cholesterol, a complex 27-carbon heterocyclic hydrocarbon, is synthesized from a 2-carbon precursor, acetyl-CoA, through the activities of more than 25 enzymes. Cholesterol is an essential component of cell membranes, and it is also the
SREBP Pathway
Figure 1, The SREBP Pathway
precursor for steroid hormones like androgens, estrogens, and glucocorticoids, as well as for bile acids. Fatty acids are linear polymers ranging in length from 16 to 24 carbons. Also synthesized from acetyl-CoA, fatty acids are incorporated into the bulk phospholipids of cell membranes, and they are the precursors of many signaling molecules, including prostaglandins. When animals ingest excess calories in the form of carbohydrate or protein, these substrates are converted into fatty acids in the liver. The fatty acids are esterified with glycerol to form triglycerides, which are transported to adipose tissue for storage.

Recently, our laboratory discovered a family of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control cholesterol and fatty acid synthesis. Unlike other transcription factors, the SREBPs are synthesized as intrinsic membrane-bound proteins of the endoplasmic reticulum (ER). After synthesis, the SREBPs form a complex with a membrane-embedded escort protein called SCAP. In lipid-depleted cells, SCAP facilitates the incorporation of SREBPs into vesicles that bud from the ER and move to the Golgi apparatus, where the SREBPs are processed sequentially by two membrane-bound proteases. The second protease cuts the SREBPs within a membrane-spanning helix in a process called Regulated Intramembrane Proteolysis (RIP). This liberates the active transcription factor domain of the SREBPs so that they can enter the nucleus and activate genes encoding enzymes required for synthesis of cholesterol and fatty acids. When cholesterol accumulates in ER membranes, SCAP undergoes a conformational change that causes it to bind to one of two ER retention proteins called Insig-1 and Insig-2. This binding prevents SCAP from escorting SREBPs to the Golgi, thereby abrogating the proteolytic processing of SREBPs. This feedback inhibition is essential to the prevention of cholesterol overproduction in animals.

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