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Gonadotropin-releasing hormone regulates atp-binding cassette g1 and g4 to transport cholesterol in the brain
thesisposted on 22.03.2017, 01:33 by Phang, Yen Li
The ATP-binding cassette (ABC) transporter family G1 and G4 play an important role in the transport of lipids, especially cholesterol across cell membranes in the brain. Gonadotropin-releasing hormone (GnRH), which is widely known to be the driving force in reproduction, has been implied to play other roles apart from its direct involvement in the reproductive cascade. One of these roles is in the regulation of metabolism, where a link between GnRH and cholesterol has long been implied but was never fully investigated. Advance teleost fishes such as tilapia (Oreochromis niloticus) in particular, express all three known subtypes of GnRH, namely GnRH1, GnRH2 and GnRH3. Moreover, the three types of receptors (GnRHR1, GnRHR2 and GnRHR3) for these GnRHs are also widely distributed in the brain. Thus, the studies documented in this thesis aimed to investigate the role of GnRH in regulating cholesterol homeostasis in the brain, with particular attention on ABCG1 and ABCG4 transporters. Two novel genes (ABCG1 and ABCG4) from the brain tissue of the tilapia fish were cloned and were used in the subsequent investigations of the role of GnRH in the control of cholesterol transport. Both ABCG1 and ABCG4 mRNAs were found to be highly expressed in the central nervous system, pituitary and gonads of tilapia. Additionally, ABCG1 mRNA was found to be highly expressed in the pituitary while ABCG4 mRNA displayed wide distribution pattern of expression across different brain regions. Both ABCG1 and ABCG4 mRNAs were also detected in all three types of GnRH neurons in the tilapia. Three forms of GnRH were applied exogenously to tilapia brain cell cultures and the effect of these GnRHs in mediating the expression of ABCG1 and ABCG4 were recorded. Both ABCG1 and ABCG4 mRNA expressions were affected (differentially up-regulated or down-regulated depending on brain region investigated) in the cells from the olfactory bulb, forebrain and pituitary. The effect of cholesterol on ABCG1 and ABCG4 mRNA expressions were also investigated through loading of exogenous cholesterol into brain cell cultures. Only ABCG1 expression was observed to up-regulated in the hindbrain region. Taken together, the results from this thesis show that ABCG1 transporter gene is regulated directly by changes in cellular cholesterol level in the brain while ABCG4 transporter gene is modulated directly by GnRH1 (in the OB) and GnRH2 (in the pituitary).