出版社：American Society for Biochemistry and Molecular Biology
摘要：Hepatic lipase (HL) plays a key role in the metabolism of plasma lipoproteins, and its level of activity requires tight regulation, given the association of both low and high levels with atherosclerosis and coronary artery disease. However, little is known about the factors responsible for HL expression. Here, we report that the human hepatic lipase gene ( LIPC ) promoter is regulated by hepatocyte nuclear factor 4α (HNF4α), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), apolipoprotein A-I regulatory protein-1 (ARP-1), and hepatocyte nuclear factor 1α (HNF1α). Reporter analysis showed that HNF4α directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4. PGC-1α is capable of stimulating the HNF4α-dependent transactivation of the LIPC promoter. ARP-1 displaces HNF4α from the DR1 site and blocks its ability to activate the LIPC promoter. Induction by HNF1α requires the HNF1 binding site and upon cotransfection with HNF4α leads to an additive effect. In addition, the in vivo relevance of HNF4α in LIPC expression is shown by the ability of the HNF4α antagonist Medica 16 to repress endogenous LIPC mRNA expression. Furthermore, disruption of Hnf4α in mice prevents the expression of HL mRNA in liver. The overall effect these transcription factors have on HL expression will ultimately depend on the interplay between these various factors and their relative intracellular concentrations.
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