Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins

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