Sterols and gene expression: control of affluence.
Intracellular and extracellular cholesterol levels are tightly maintained within a narrow concentration range by an intricate transcriptional control mechanism. Excess cholesterol can be converted into oxysterols, signaling molecules, which modulate the activity of a number of transcription factors, as to limit accumulation of excess of cholesterol. Two key regulatory pathways are affected by oxysterols. The first pathway involves the uptake and de novo synthesis of cholesterol and is controlled by the family of sterol response element binding proteins, whose activity is regulated by a sterol-dependent feedback mechanism. The second pathway, which only recently has become a topic of interest, involves the activation by a feedforward mechanism of cholesterol utilization for either bile acid or steroid hormone synthesis by oxysterol-activated nuclear receptors, such as liver X receptor and steroidogenic factor-1. Furthermore, biosynthesis and enterohepatic reabsorption of bile acids are regulated by the farnesol X receptor, a receptor activated by bile acids. Both the feedback inhibition of cholesterol uptake and production and the stimulation of cholesterol utilization will ultimately result in a lowering of the intracellular cholesterol concentration and allow for a fine-tuned regulation of the cholesterol concentration.
Schoonjans
K
K
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.
Brendel
C
C
Mangelsdorf
D
D
Auwerx
J
J
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D022762:CCAAT-Enhancer-Binding Proteins / Q000494:pharmacology*; D002784:Cholesterol / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism; D051717:Fushi Tarazu Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects*; D018398:Homeodomain Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D054339:Steroidogenic Factor 1; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D022762:CCAAT-Enhancer-Binding Proteins; D002784:Cholesterol; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D054339:Steroidogenic Factor 1; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated