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M511050200v1
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Papers In Press, published online ahead of print November 9, 2005
J. Biol. Chem, 10.1074/jbc.M511050200
Submitted on October 11, 2005
Revised on November 4, 2005
Accepted on November 9, 2005

Regulation of HMG CoA reductase promoter by nuclear receptors LRH-1 and SHP: A mechanism for differential regulation of cholesterol synthesis and uptake

Shrimati Datta, Li Wang, David D. Moore, and Timothy F. Osborne

Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697-3900

Corresponding Author: tfosborn{at}uci.edu

Cholesterol homeostasis in mammals involves pathways for biosynthesis, cellular uptake and hepatic conversion to bile acids. Key genes for all three pathways are regulated by negative feedback control. Uptake and biosynthesis are directly regulated by cholesterol through its inhibition of the proteolytic activation of the sterol regulatory element binding proteins (SREBPs). Whereas the conversion of cholesterol into bile acids in the liver is regulated through the bile acid dependent induction of the negative acting small heterodimer partner (SHP) nuclear receptor. In this report we show that SHP also directly regulates cholesterol biosynthesis through inhibition of HMG CoA reductase but has no effect on LDL receptor expression. This has significant metabolic significance as it provides both a mechanism to independently regulate cholesterol synthesis from uptake, an essential regulatory feature known to occur in vivo, and a pathway for direct regulation of cholesterol biosynthesis by bile acids. This latter feature ensures that the early phase of bile acid synthesis (pre-cholesterol) is in metabolic communication with the later stages of the pathway to properly regulate whole pathway flux. This highlights an important regulatory feature that is shared with other key branched, multi-enzyme pathways such as glycolysis where pathway outflow through pyruvate kinase is regulated by the concentration of a key early intermediate, fructose 1,6 bisphosphate.


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