In this thesis, the effects of GH and PPARα on lipid metabolism have been investigated, especially with respect to hepatic genes involved in lipogenesis and VLDL assembly.
• The importance of increased insulin levels for the effects of GH on lipoprotein metabolism was investigated in Hx rats. GH increased the triglyceride secretion rate and content in the liver (Figure 8), which could be explained by increased gene expression of enzymes in lipogenesis. Insulin suppressed the effect of GH on the hepatic triglyceride secretion rate and content, but this was not due to decreased expression of SCD-1, FAS or MTP. Insulin also suppressed the effect of GH on SREBP-1c mRNA. The GH-antagonistic effect of insulin may therefore be explained by changed expression of other SREBP-1c regulated genes or decreased availability of FFA. In conclusion, insulin does not mediate the effects of GH but inhibits the stimulatory effect of GH on hepatic SREBP-1c expression and hepatic triglyceride secretion rate and content.
Figure 8. The effects of continuous GH (GHc) administration in this thesis. *TG (triglyceride) synthesis was measured as total TG biosynthesis in the whole cell (results from Sjöberg et al, 1996 [136]).
apoB MTP
TG ER lumen
TG Pre-VLDL
TG
TG
Cytosol
TG TG
FAS, GPAT mRNA
+ GHc
+
+ +
+ +
TG synthesis*
+ +
TG synthesis*
• The regulation of hepatic lipogenic genes and MTP by the sex-differentiated GH secretory pattern was studied in Hx rats administered GH in a mode that mimics either the female or male plasma pattern of GH. FAS and GPAT mRNA levels were increased in females compared to males and specifically upregulated by female-like GH administration, probably due to decreased insulin sensitivity. SCD-1 was not sex-differentiated and increased by GH irrespective of administration mode. The MTP expression was higher in female rats due to the female GH secretory pattern. In conclusion, increased expression of FAS, GPAT and MTP could help to explain the previously described stimulatory effects of female sex and the female GH secretory pattern on VLDL assembly and secretion (Figure 8).
• Treatment of mice and rats with a PPARα agonist (WY) increased MTP expression and activity in mouse and rat liver. Incubation of primary cultures of mouse and rat hepatocytes with WY also increased MTP expression. By using primary hepatocyte cultures from PPARα KO mice, this effect of WY was shown to be PPARα specific. In rat hepatocytes incubated with WY, MTP protein expression and apoB-100 secretion increased between 24 and 72 h of incubation. In conclusion, PPARα activation increases MTP expression and activity that could explain the increased apoB-100 secretion from hepatocytes following PPARα activation (Figure 9).
Figure 9. The effects of PPARα treatment in this thesis. *Results from Lindén et al, 2002 [92]. TG (triglyceride) synthesis was measured as total TG biosynthesis in the whole cell.
--ACKNOWLEDGEMENTS
I am grateful to all the persons who in one way or another have contributed to this thesis or who have made my life as a PhD student much more enjoyable. I would especially like to thank:
Jan Oscarsson, my supervisor, for all your support and excellent guidance throughout the years. You have shared both your great knowledge and enthusiasm for science with me, which I have very much appreciated.
Past and present members of the Endocrine division, for all the good times and for creating such a nice atmosphere to work in. It was sad leaving you…
…but I am very happy for the warm welcome at Wallenberg laboratory! My time here has been a pleasure thanks to all nice people and the cheerful atmosphere!
All co-authors, for help with lab work and valuable comments on the manuscripts.
My present fellow PhD students, Anna Ljungberg, for being a good friend and for sharing my passion for apples and aversion for cold, and Ulrika Edvardsson, for nice company in the lab and for being my personal Maniatis.
My former fellow PhD students, Linda Carlsson, for good company in the “booth”
and for the way you kept the Endocrine division in order, Daniel Lindén, for nice collaboration that is still ongoing, and Fredrik Frick, for your sense of humour that makes everyone feel good at work.
Mikael Alsterholm, for being such a nice person and for always drinking tea with me.
I miss you at the lab (are you coming back soon?)!
Heimir Snorrason, the enchanting wizard of computers, for invaluable help with everything concerning computers. I have really appreciated all your kind help!
All my friends outside the lab - no one mentioned, no one forgotten. I’m sorry that I have been asocial the last couple of months… Now I will definitively try to spend more time with you, my excellent friends!
Jonas Boström, for all the fun we had throughout the years and for being my best friend. Especially many thanks for your excellent Thai food and the warm bath that saved me from the radioactivity disaster.
My parents, Ulla and Torkel, for all your love and for always always being there.
Kajsa, the best sister you can think of! Thanks for being such a cool and kind sister (except when you don’t get food in time) and, of course, for regularly getting rid of
“the ball”.
Sandra, for endless love and support, thank you for everything.
And remember, “Acknowledgements” is NOT the important part of a thesis! Now go on read from the beginning…
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