Phosphorylation of sterol regulatory element-binding protein (SREBP)-1a links growth hormone action to lipid metabolism in hepatocytes.
OBJECTIVE
Increased lipid accumulation in cells and tissues is a key phenomenon in the development of obesity, insulin resistance, and atherosclerosis. In the regulation of lipid content of cells and tissues the SREBPs play a dominant role as transcription factors.


METHODS
Since growth hormone (GH) affects lipid metabolism and function of fat as well as liver cells, we have investigated the role of SREBP-1a, SREBP-1c and SREBP-2 in the gene regulatory action of GH in the human liver cell line HepG2 and primary mouse hepatocytes.


RESULTS
These experiments showed that SREBP-1a couples the stimulatory effect of GH on cholesterol regulated genes, e.g. LDL receptor gene, via sterol sensitive binding cis-element (sre-1). This effect was not depending on RNA expression, but related to phosphorylation of SREBP-1a protein. The result was supported by experiments with the mutant variant SREBP-1a S117A, which is not phosphorylated by Erk-MAP kinases. To analyse a possible role of GH-induced SREBP-1a phosphorylation in cellular physiology we investigated an expression profile of genes coding for central players in lipid transport or lipid metabolism as well as for transcription factors by real time PCR in primary mouse hepatocytes and human hepatoma cell line stably overexpressing the mature form of SREBP-1a or mutated form.


CONCLUSIONS
These experiments emphasize the role SREBP-1a and its phosphorylation for gene regulatory effects of GH.
Kotzka
Jorg
J
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Aufm Hennekamp 65, 40225 Duesseldorf, Germany.
Knebel
Birgit
B
Avci
Haluk
H
Jacob
Sylvia
S
Nitzgen
Ulrike
U
Jockenhovel
Friedrich
F
Heeren
Joerg
J
Haas
Jutta
J
Muller-Wieland
Dirk
D
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008954:Models, Biological; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D008055:Lipids; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D013006:Growth Hormone; D002784:Cholesterol