Sterol-regulatory-element binding protein inhibits upstream stimulatory factor-stimulated hepatic lipase gene expression.
Hepatic lipase (HL) not only plays an important role in plasma lipoprotein transport, but may also affect intracellular lipid metabolism. We hypothesize that HL expression is regulated as an integral part of intracellular lipid homeostasis. Addition of oleate (1 mM) to HepG2 cells increased HL secretion to 134+/-14% of control (p<0.02), and increased the transcriptional activity of a 698-bp HL promoter-reporter construct two-fold. Atorvastatin (10 microM) abolished the oleate stimulation. The transcriptional activity of a sterol-regulatory-element binding protein (SREBP)-sensitive HMG-CoA synthase promoter construct was reduced 50% by oleate, and increased 2-3-fold by atorvastatin. Co-transfection with an SREBP-2 expression vector reduced HL promoter activity and increased HMG-CoA synthase promoter activity. Upstream stimulatory factors (USF) are also implicated in maintenance of lipid homeostasis. Co-transfection with a USF-1 expression vector stimulated HL promoter activity 4-6-fold. The USF-stimulated HL promoter activity was not further enhanced by oleate, but almost completely prevented by atorvastatin or co-transfection with the SREBP-2 vector. Opposite regulation by USF-1 and SREBP-2 was also observed with a 318-bp HL promoter construct that lacks potential SRE-like and E-box binding motifs. We conclude that the opposite regulation of HL expression by fatty acids and statins is mediated via SREBP, possibly through interaction with USF.
Botma
Gert-Jan
GJ
COEUR Cardiovascular Research School, Department of Biochemistry, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
van Deursen
Diederik
D
Vieira
Delfina
D
van Hoek
Mandy
M
Jansen
Hans
H
Verhoeven
Adrie J M
AJ
D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006538:Heptanoic Acids / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism*; D008113:Liver Neoplasms; D019301:Oleic Acid / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000378:metabolism*
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids; C504173:LIPC protein, human; D011758:Pyrroles; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D019301:Oleic Acid; D002784:Cholesterol; D000069059:Atorvastatin; D008049:Lipase