The molecular mechanism of how hepatocytes maintaincholesterol homeostasis has become much more transparentwith the discovery of sterol regulatory element binding proteins(SREBPs)in recent years.These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper(bHLH-Zip)family of transcription factors.They activate the expressionof at least 30 genes involved in the synthesis of cholesteroland lipids.SREBPs are synthesized as precursor proteins inthe endoplasmic reticulum(ER),where they form a complexwith another protein,SREBP cleavage activating protein(SCAP).The SCAP molecule contains a sterol sensory domain.Inthe presence of high cellular sterol concentrations SCAP confinesSREBP to the ER.With low cellular concentrations,SCAP escortsSREBP to activation in the Golgi.There,SREBP undergoestwo proteolytic cleavage steps to release the mature,biologicallyactive transcription factor,nuclear SREBP(nSREBP).nSREBPtranslocates to the nucleus and binds to sterol responseelements(SRE)in the promoter/enhancer regions of targetgenes.Additional transcription factors are required to activatetranscription of these genes.Three different SREBPs areknown,SREBPs-1a,-1c and -2.SREBP-1a and -1c are isoformsproduced from a single gene by alternate splicing.SREBP-2is encoded by a different gene and does not display anyisoforms.It appears that SREBPs alone,in the sequencedescribed above,can exert complete control over cholesterolsynthesis,whereas many additional factors(hormones,cytokines,etc.) are required for complete control of lipidmetabolism.Medicinal manipulation of the SREBP/SCAPsystem is expected to prove highly beneficial in themanagement of cholesterol-related disease.Weber LW,Boll M,Stampfl A.Maintaining cholesterol homeostasis:Sterol regulatory element-binding proteins.World J Gastroenterol2004;10(21):3081-3087http://www.wjgnet.com/1007-9327/10/3081.asp The molecular mechanism of how hepatocytes maintaincholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins are members of the basic helix-loop-helix-leucine zipper (bHLH-Zip) family of transcription factors. The activation of the expression of at least 30 genes involved in the synthesis of cholesteroland lipids. SREBPs are synthesized as precursor proteins inthe endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. Inthe presence of high cellular sterol concentrations SCAP confinesSREBP to the ER. Low-cellular concentrations, SCAP escortsSREBP to activation in the Golgi. Here, SREBP undergoes proteolytic cleavage steps to release the mature, biologicallyactive transcription factor, nuclear SREBP (nSREBP) .nSREBPtranslocates to the nucleus and binds to sterol response elements (SR E) in the promoter / enhancer regions of targetgenes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs areknown, SREBPs-1a, -1c and -2.SREBP-1a and-1c are isoform production from a single gene by alternate splicing. SREBP-2is encoded by a different gene and does not display anyisomes. It appears that SREBPs alone, in the sequencedescribed above, can exert complete control over cholesterolsynthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP / SCAPsystem is expected to prove highly beneficial in the management of cholesterol-related disease. Webber LW, Boll M, Stampfl A. Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins. World J Gastroenterol 2004; 10 (21): 3081-3087http: //www.wjgnet.com/1007-9327/10/3081.asp