Energy storage and consumption of the healthy human body are well geared to the needs under physiological conditions. Any disturbances in this balance can result in metabolic diseases such as obesity. A key feature of metabolic disorders is an abnormal lipid profile, as characterized by elevated serum triglycerides, elevated low density lipoprotein (LDL) cholesterol and reduced high density lipoprotein (HDL) cholesterol. These alterations can increase the risk for the development of type 2 diabetes or atherosclerotic cardiovascular diseases. In this study, the transcriptional co-factor transforming growth factor beta1-stimulated clone 22 D1 (TSC22D1) was identified as novel regulator of systemic cholesterol metabolism. Acute or chronic knockdown of TSC22D1 in livers of wild-type mice resulted in a significant decrease of serum HDL cholesterol and mildly elevated liver cholesterol. These changes are caused by a reduced expression of key genes involved in cholesterol efflux such as Apolipoprotein A1 (ApoA1), or transporters as ATP binding cassette protein A1 (ABCA1), ABCG5 and ABCG8. Interestingly, serum HDL cholesterol could be elevated by overexpression of hepatic TSC22D1 in wild type mice. Moreover, TSC22D1 expression was found to be differentially regulated in mouse models of opposing energy supply. Whereas levels of TSC22D1 transcripts were significantly reduced in states of energy wasting as in cancer cachexia, they were increased by energy surplus as under obese conditions. Along these lines, hepatic TSC22D1 expression was increased in ob/ob mice, which are highly resistant to the development of atherosclerosis due to their elevated HDL levels. Again, TSC22D1 knockdown significantly lowered serum HDL cholesterol and reduced expression of ApoA1, ABCA1, ABCG5 and ABCG8. Intriguingly, plasma concentrations of HDL/ApoA1 inversely correlate with the risk for atherosclerotic cardiovascular disease in humans. Thus, hepatic TSC22D1 transcription factor complex may represent an interesting new target for beneficial manipulation of HDL cholesterol levels.
|Supervisor:||Melchior, Prof. Dr. Frauke|
|Date of thesis defense:||21 November 2013|
|Date Deposited:||19 Dec 2013 09:09|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Subjects:||570 Life sciences|